Benzodiazepine and pyridodiazepine derivatives

ABSTRACT

The present application relates to benzodiazepine and pyridodiazepine derivatives of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , X 1 , Y 1 , Y 2 , and Y 3  are as defined in the specification. The present application also relates to compositions comprising such compounds, and methods of treating disease conditions using such compounds and compositions, and methods for identifying such compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication No. 61/326,696, filed on Apr. 22, 2010, and U.S. ProvisionalPatent Application No. 61/366,959, filed on Jul. 23, 2010, each of whichis herein incorporated by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

FIELD OF THE INVENTION

The present invention relates to benzodiazepine and pyridodiazepinederivatives, compositions comprising these benzodiazepine andpyridodiazepine derivatives, methods of preventing or treating diseaseconditions such as neurodegeneration or neuropsychiatric disorders usingsuch compounds and compositions, and processes for preparing suchcompounds and compositions.

BACKGROUND OF THE INVENTION

Treatment of dementias of various types, such as but not limited to,Alzheimer's disease (AD), Parkinson's disease, Huntington's disease andother forms, continue to be unmet medical needs. Alzheimer's disease isthe most common form of dementia, wherein loss of memory and otherintellectual abilities are serious enough to interfere with dailyliving. Alzheimer's disease is an age-related neurodegenerative disordercharacterized by progressive loss of memory accompanied with cholinergicneurodegeneration (Kar, S.; Quirion, R. Amyloid β peptides and centralcholinergic neurons: functional interrelationship and relevance toAlzheimer's disease pathology. Prog. Brain Res. 2004, 145(Acetylcholinein the Cerebral Cortex), 261-274.). This disease accounts for over 50%of all progressive cognitive impairment in elderly patients. Theprevalence increases with age. Alzheimer's disease is classified by itsseverity as mild, moderate and severe. The pathological hallmarks of ADinclude neuronal dysfunction/death, accumulation of senile plaquesextracellularly and neurofibrillary tangles (NFTs) intrancuronally.Several hypotheses have been put forth to explain the pathophysiology ofthis disease, including aberrant β-amyloid (Aβ) metabolism,hyperphosphorylation of cytoskeletal proteins, genetic predispositionsuch as mutations in genes coding for presenilin-1 and -2 (PS-1 andPS-2) and amyloid precursor protein (APP), apolipoprotein E genotype,oxidative stress, excitotoxicity, inflammation and abnormal cell cyclere-entry. However to date, none of these hypotheses is sufficient toexplain the diversity of biochemical and pathological abnormalities inAD.

Two pathological hallmarks of AD are generally recognized: senileplaques composed of β-amyloid peptide 1-42 (Aβ₁₋₄₂) and neurofibrillarytangles (NFTs) formed by abnormal polymerization ofmicrotubule-associated protein tau (Walsh, D. M.; Selkoe, D. J.Deciphering the molecular basis of memory failure in Alzheimer'sdisease. Neuron 2004, 44(1), 181-193.). While the precise causeunderlying AD-related memory loss and cognitive changes remains to befully elucidated, there is evidence indicating that pathologicalassemblies of Aβ₁₋₄₂ cause diverse forms of AD and that tau plays a roleincluding in mechanisms leading to Aβ₁₋₄₂-induced neurodegeneration.More recent evidence from studies using transgenic animals suggests thattau pathology exacerbates neurodegenerative and cognitive processes inthe presence of Aβ₁₋₄₂ (Oddo, S.; Caccamo, A.; et al. Temporal Profileof Amyloid-β (Aβ) Oligomerization in an in Vivo Model of AlzheimerDisease: a link between Aβ and tau pathology. J. Biol. Chem. 2006,281(3), 1599-1604.). In addition to Aβ and tau, dysregulation of calciumhomeostasis also plays an integral role in the pathophysiology of AD(Green, K. N.; LaFerla, F. M. Linking calcium to Aβ and Alzheimer'sdisease. Neuron 2008, 59(2), 190-194.). It is becoming evident thatdysregulation of mitochondrial function and resultant altered cellularhomeostasis increasingly contributes to the pathology ofneurodegenerative diseases such as AD (Moreira, P. I.; Santos, M. S.; etal. Is mitochondrial impairment a common link between Alzheimer'sdisease and diabetes? A matter under discussion. Trends Alzheimer's Dis.Res. 2006, 259-279. Beal, M. F. Mitochondria and neurodegeneration.Novartis Found. Symp. 2007, 287(Mitochondrial Biology), 183-196. Reddy,P. H.; Beal, M. F. Amyloid beta, mitochondrial dysfunction and synapticdamage: implications for cognitive decline in aging and Alzheimer'sdisease. Trends Mol. Med. 2008, 14(2), 45-53.).

Mitochondria play major roles in bioenergetics and cell death/survivalsignaling of the mammalian cell as they are ‘gatekeepers of life anddeath’. Mitochondrial dysfunction contributes to the pathogenesis ofvarious neurodegenerative diseases with pathophysiological consequencesat multiple levels including at the level of calcium-drivenexcitotoxicity. One of the primary mitochondrial mechanisms is themitochondrial permeability transition pores (MPTP) that represent amultiprotein complex derived from components of inner and outermitochondrial membrane. The pores regulate transport of ions andpeptides in and out of mitochondria, and their regulation is associatedwith mechanisms for maintaining cellular calcium homeostasis. A deficitin mitochondria is the earliest feature of neurodegenerative diseases.One general characteristic of aging and neurodegeneration is an increasein the number of neuronal cells undergoing signs of apoptoticdegeneration. A key role for this apoptotic process is attributable tothe mitochondrial permeability transition pore, which provides transportin and out of mitochondria for both calcium ions and compounds with lowmolecular weight. It has been proposed that MPTP is a multiproteincomplex with the outer membrane fragment including porin (avoltage-dependent ion channel), anti-apoptotic proteins of the Bcl-2family, and the peripheral benzodiazepine receptor. The inner fragmentof MPTP contains an adenine nucleotide translocator and cyclophilin,which may interact with proapoptotic proteins of the Bax familyInhibition of mitochondrial calcium uptake and/or blocking of MPTP mayprotect cells against the development of apoptosis in the presence ofpathological factors such as excitotoxins and anti-oxidants. Indirectmodulation of MPTP via kinase pathways is also known wherein glycogensynthase kinase-3β (GSK3β) mediates convergence of protection signalingto inhibit the mitochondrial MPTP (Juhaszova, M.; Zorov, D. B.; et al.Glycogen synthase kinase-3β mediates convergence of protection signalingto inhibit the mitochondrial permeability transition pore. J. Clin.Invest. 2004, 113(11), 1535-1549. Juhaszova, M.; Wang, S.; et al. Theidentity and regulation of the mitochondrial permeability transitionpore: where the known meets the unknown. Ann. N.Y. Acad. Sci. 2008, 1123(Control and Regulation of Transport Phenomena in the Cardiac System),197-212.) and mitochondrial localization during apoptosis (Linseman, D.A.; Butts, B. D.; et al. Glycogen synthase kinase-3β (phosphorylates Baxand promotes its mitochondrial localization during neuronal apoptosis.J. Neurosci. 2004, 24(44), 9993-10002.). Furthermore, calcium-dependentactivation of MPTP in brain mitochondria enhances with age and may playan important role in age related neurodegenerative disorders.

Neuroprotective effects of agents have been linked to various cellularprocesses including inhibition of mitochondrial MPTPs. For example, theneuroprotective effects of 4-azasteroids parallel the inhibition of themitochondrial transition pore (Soskic, V.; Klemm, M.; et al. Aconnection between the mitochondrial permeability transition pore,autophagy, and cerebral amyloidogenesis. J. Proteome Res. 2008, 7(6):2262-2269.). In vivo administration of MPTP inhibitor,1-(3-chlorophenyl)-3-phenyl-pyrrole-2,5-dione to a mouse model ofmultiple sclerosis significantly prevented the development of thedisease (Pelicci, P., Giorgio, M.; et al. MPTP inhibitors for blockadeof degenerative tissue damages. WO 2008067863A2).

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to compounds of having aformula of (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein

R¹ is selected from the group consisting of hydrogen, alkyl,alkylcarbonyl, haloalkyl, G¹, —(CR^(4a)R^(5a))_(m)-G¹, —C(O)-G¹,—S(O)₂G¹, —C(O)OR⁶ and —C(O)NR⁷R⁸; wherein R¹ is other than hydrogen,alkyl, alkylcarbonyl, or haloalkyl when one of Y¹ or Y² is CH₂ and theother is NR⁹;

R², R³, R⁴, and R⁵ are each independently hydrogen, alkyl, alkenyl,alkynyl, halogen, cyano, —NO₂, —OR^(1a), —S(O)₂R^(2a), —C(O)OR^(1a), orhaloalkyl;

R⁶ is alkyl or —(CR^(4a)R^(5a))_(m)-G¹;

R⁷ and R⁸ are independently hydrogen, alkyl, G¹, or—(CR^(4a)R^(5a))_(m)-G¹;

R⁹ is hydrogen or alkyl;

R^(1a), at each occurrence, is independently hydrogen, alkyl, haloalkyl,or —(CR^(4a)R^(5a))_(m)-G¹;

R^(2a), at each occurrence, is independently alkyl, haloalkyl, or G¹;

R^(4a) and R^(5a), at each occurrence, are each independently hydrogen,halogen, alkyl, or haloalkyl, or R^(4a) and R^(5a) together with thecarbon to which they are attached form a cycloalkyl;

R^(1b), at each occurrence, is independently hydrogen, alkyl, orhaloalkyl;

R^(2b), at each occurrence, is independently alkyl, cyanoalkyl orhaloalkyl;

G¹, at each occurrence, is independently aryl or heteroaryl, whereineach G¹ is independently unsubstituted or substituted with 1, 2, 3, 4,or 5 substituents selected from the group consisting of alkyl, alkenyl,halogen, cyano, —NO₂, —OR^(1b), —S)O)₂R^(2b), —C(O)OR^(1b),—(CR^(4a)R^(5a))_(m)—N(R^(1b))₂, and haloalkyl;

G², at each occurrence, is independently cycloalkyl or heterocycle,wherein each G² is independently unsubstituted or substituted with 1, 2,3, 4, or 5 substituents selected from the group consisting of alkyl,alkenyl, halogen, cyano, —NO₂, —OR^(1b), S(O)₂R^(2b); —C(O)OR^(1b),—C(O)R^(2b), —C(O)N(R^(1b))₂, haloalkyl, and oxo;

m, at each occurrence, is independently 1, 2, 3, 4, or 5;

X¹ is N or CR⁵;

one of Y¹ or Y² is CH₂ and the other is selected from the groupconsisting of NR⁹, N-G¹, N—(CR^(4a)R^(5a))_(m)-G¹,N⁺-[(CR^(4a)R^(5a))_(m)-G¹]₂, NC(O)—R^(2b),NC(O)_(CR^(4a)R^(5a))_(m)-G¹, NC(O)—(CR^(4a)R^(5a))_(m)—W¹,NC(O)—CH═CH-G¹, NC(O)-G¹, NC(O)-G²-G¹, N-G², N-G²-C(O)-G¹,N—(CR^(4a)R^(5a))_(m)-G², NC(O)—(CR^(4a)R^(5a))_(m)-G², NC(O)-G²,NC(O)NH—W³, NC(O)N(R^(2b))—W³, andNC(O)N(R^(1b))—(CR^(4a)R^(5a))_(m)—W²; wherein

-   -   W¹ is NHC(O)G¹ or —O—(CR^(4a)R^(5a))_(m)—R^(1b);    -   W² is G¹, G², N(R^(1b))₂; R^(1b), or        —O—(CR^(4a)R^(5a))_(m)—R^(1b);    -   W³ is R^(1b), G¹ or G²; and

Y³ is CH₂ or C(O).

In another aspect, the present invention relates to pharmaceuticalcompositions comprising a therapeutically effective amount of at leastone compound(s) having a formula of (I), described above orpharmaceutically acceptable salts thereof, in combination with at leastone pharmaceutically acceptable carrier.

The present invention can also include use of a compound of formula (I)as neuroprotective agent for the prevention or treatment of aneurological disorder or condition. The method includes administering atherapeutically effective amount of at least one compound of formula(I), to a subject in need of treatment thereof. The neurologicaldisorder or condition can include, but is not limited to,neurodegeneration disorders, neuropsychiatric disorder and painconditions, brain injuries, stroke and other acute and chronic neuronalinjuries or degenerative conditions. The neurological disorder orcondition can include, for example, conditions associated, at least inpart, with mitochondrial dysfunction and/or neuronal apoptosis in thecentral nervous system.

In still yet another aspect, the present invention relates to the use ofa compound of formula (I), or a pharmaceutically acceptable salt thereofin the manufacture of a medicament for the prevention or treatment ofthe neurodegeneration disorders described above, alone or in combinationwith at least one pharmaceutically acceptable carrier.

The compounds of formula (I), compositions comprising these compounds,and methods for preventing or treating neurodegenerative orneuropsychiatric disorders by administering these compounds orpharmaceutical compositions are further described herein.

These and other objects of the invention are described in the followingparagraphs. These objects should not be deemed to narrow the scope ofthe invention.

DETAILED DESCRIPTION

In one aspect, the present invention relates to compounds having aformula (I) as shown below:

wherein R¹, R², R³, R⁴, X¹, Y¹, Y² and Y³ are as defined above in theSummary of the Invention.

In another aspect, the present invention relates to compositioncomprising compounds having a formula (I) as described above and atleast one pharmaceutically acceptable carrier.

In still yet another aspect, the present invention relates to methodsfor preventing and treating disease conditions, such asneurodegeneration disorders or neuropsychiatric disorders, usingcompounds having a formula of formula (I) as described above.

In still yet another aspect, the present invention relates to the use ofcompounds having a formula (I) in the manufacture of a medicament forthe prevention or treatment of the disease conditions, such asneurodegeneration disorders or neuropsychiatric disorders, describedabove, alone or in combination with at least one pharmaceuticallyacceptable carrier.

In various embodiments, the present invention provides at least onevariable that occurs more than one time in any substituent or in thecompound of the present invention or any other formulae herein.Definition of a variable on each occurrence is independent of itsdefinition at another occurrence. Further, combinations of substituentsare permissible only if such combinations result in stable compounds.Stable compounds are compounds, which can be isolated from a reactionmixture.

a. DEFINITIONS

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond formed by the removal of twohydrogens. Representative examples of alkenyl include, but are notlimited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” denotes a divalent group derived from a straightor branched chain hydrocarbon of 2 to 4 carbon atoms and contains atleast one carbon-carbon double. Representative examples of alkenyleneinclude, but are not limited to, —CH═CH— and —CH₂CH═CH—.

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term “loweralkyl” or “C₁₋₆ alkyl” means a straight or branched chain hydrocarboncontaining 1 to 6 carbon atoms. The term “C₁₋₃ alkyl” means a straightor branched chain hydrocarbon containing 1 to 3 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-hcptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylene” denotes a divalent group derived from a straight orbranched chain hydrocarbon 1 to 10 carbon atoms. Representative examplesof alkylene include, but are not limited to, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl” as used herein, means phenyl or a bicyclic aryl. Thebicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl,or a phenyl fused to a monocyclic cycloalkenyl. Representative examplesof the aryl groups include, but are not limited to, dihydroindenyl,indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. Thebicyclic aryl is attached to the parent molecular moiety through anycarbon atom contained within the bicyclic ring system. The aryl groupsof the present invention can be unsubstituted or substituted.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of arylalkyl include,but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “cyano” as used herein, means a —CN group.

The term “cyanoalkyl” as used herein, means a cyano group, as definedherein, appended to the parent molecular moiety through an alkylenegroup, as defined herein. Representative examples of cyanoalkyl include,but are not limited to, cyanomethyl, 2-cyanoethyl, and 3-cyanopropyl.

The term “cycloalkenyl” as used herein, means a monocyclic or bicyclicring system containing from 3 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of monocyclic ring systems include, but are notlimited to, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclohexadien-1-yland 3-cyclopenten-1-yl. Bicyclic ring systems are exemplified by amonocyclic cycloalkenyl ring system which is fused to another monocycliccycloalkyl ring as defined herein, a monocyclic aryl ring as definedherein, a monocyclic heterocycle as defined herein or a monocyclicheteroaryl as defined herein. The bicyclic ring systems of the presentinvention must be appended to the parent molecular moiety through anavailable carbon atom within the cycloalkenyl ring. Representativeexamples of bicyclic ring systems include, but are not limited to,4,5-dihydro-benzo[1,2,5]oxadiazole, 3a,4,5,6,7,7a-hexahydro-1H-indenyl,1,2,3,4,5,6-hexahydro-pentalenyl,1,2,3,4,4a,5,6,8a-octahydro-pentalenyl.

The term “cycloalkyl” or “cycloalkane” as used herein, means amonocyclic, a bicyclic, or a tricyclic cycloalkyl. The monocycliccycloalkyl is a carbocyclic ring system containing three to eight carbonatoms, zero heteroatoms and zero double bonds. Examples of monocyclicring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. The bicyclic cycloalkyl is a monocycliccycloalkyl fused to a monocyclic cycloalkyl ring, or a bridgedmonocyclic ring system in which two non-adjacent carbon atoms of themonocyclic ring are linked by an alkylene bridge containing one, two,three, or four carbon atoms. Representative examples of bicyclic ringsystems include, but are not limited to, bicyclo[3.1.1]heptane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane,bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Tricyclic cycloalkylsare exemplified by a bicyclic cycloalkyl fused to a monocycliccycloalkyl, or a bicyclic cycloalkyl in which two non-adjacent carbonatoms of the ring systems are linked by an alkylene bridge of 1, 2, 3,or 4 carbon atoms. Representative examples of tricyclic-ring systemsinclude, but are not limited to, tricyclo[3.3.1.0^(3,7)]nonane(octahydro-2,5-methanopentalene or noradamantane), andtricyclo[3.3.1.1^(3,7)]decane (adamantane). The monocyclic, bicyclic,and tricyclic cycloalkyls can be unsubstituted or substituted, and areattached to the parent molecular moiety through any substitutable atomcontained within the ring system.

The term “halo” or “halogen” as used herein, means Cl, Br, I, or F.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. Representative examples of haloalkyl include, butare not limited to, fluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,trifluoromethyl, difluoromethyl, pentafluoroethyl,2-chloro-3-fluoropentyl, and trifluoropropyl such as3,3,3-trifluoropropyl.

The term “heterocycle” or “heterocyclic” as used herein, means amonocyclic heterocycle, a bicyclic heterocycle, or a tricyclicheterocycle. The monocyclic heterocycle is a three-, four-, five-, six-,seven-, or eight-membered ring containing at least one heteroatomindependently selected from the group consisting of O, N, and S. Thethree- or four-membered ring contains zero or one double bond, and oneheteroatom selected from the group consisting of O, N, and S. Thefive-membered ring contains zero or one double bond and one, two orthree heteroatoms selected from the group consisting of O, N and S. Thesix-membered ring contains zero, one or two double bonds and one, two,or three heteroatoms selected from the group consisting of O, N, and S.The seven- and eight-membered rings contains zero, one, two, or threedouble bonds and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. Representative examples of monocyclicheterocycles include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyridazin-3(2H)-onyl,pyridin-2(1H)-onyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclicheterocycle is a monocyclic heterocycle fused to a phenyl group, or amonocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclicheterocycle fused to a monocyclic cycloalkenyl, or a monocyclicheterocycle fused to a monocyclic heterocycle, or a bridged monocyclicheterocycle ring system in which two non adjacent atoms of the ring arelinked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or analkenylene bridge of two, three, or four carbon atoms. Representativeexamples of bicyclic heterocycles include, but are not limited to,benzopyranyl, 1,4-benzoxazinyl, benzothiopyranyl, chromanyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl,octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclicheterocycles are exemplified by a bicyclic heterocycle fused to a phenylgroup, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or abicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclicheterocycle fused to a monocyclic heterocycle, or a bicyclic heterocyclein which two non adjacent atoms of the bicyclic ring are linked by analkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridgeof two, three, or four carbon atoms. Examples of tricyclic heterocyclesinclude, but not limited to, octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantanc(2-oxatricyclo[3.3.1.1^(3,7)]decanc). The monocyclic, bicyclic, andtricyclic heterocycles are connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within the rings,and can be unsubstituted or substituted.

The term “heteroaryl” as used herein, means a monocyclic heteroaryl or abicyclic heteroaryl. The monocyclic heteroaryl is a five- orsix-membered ring. The five-membered ring contains two double bonds. Thefive-membered ring may contain one heteroatom selected from O or S; orone, two, three, or four nitrogen atoms and optionally one oxygen orsulfur atom. The six-membered ring contains three double bonds and one,two, three or four nitrogen atoms. Representative examples of monocyclicheteroaryl include, but are not limited to, furanyl, imidazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, 1,2-oxazolyl, 1,3-oxazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl,tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, andtriazinyl. The bicyclic heteroaryl consists of a monocyclic heteroarylfused to a phenyl, or a monocyclic heteroaryl fused to a monocycliccycloalkyl, or a monocyclic heteroaryl fused to a monocycliccycloalkenyl, or a monocyclic heteroaryl fused to a monocyclicheteroaryl, or a monocyclic heteroaryl fused to a monocyclicheterocycle. Representative examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzodiazepinyl, benzofuranyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl,6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-c]pyridinyl, imidazo[1,2-a]pyrimidinyl, indazolyl, indolyl,isoindolyl, isoquinolinyl, naphthyridinyl, pyridodiazepinyl,pyridoimidazolyl, pyrido[1,2-c]pyrimidin-4-onyl, quinoxalinyl,quinazolinyl, quinolinyl, thiazolo[5,4-b]pyridin-2-yl,thiazolo[5,4-d]pyrimidin-2-yl, and 5,6,7,8-tetrahydroquinolin-5-yl. Themonocyclic and bicyclic heteroaryl groups of the present invention canbe substituted or unsubstituted and are connected to the parentmolecular moiety through any carbon atom or any nitrogen atom containedwithin the ring systems.

The term “heteroatom” as used herein, means a nitrogen, oxygen, orsulfur atom.

The term “hydroxyl” or “hydroxy” as used herein, means an —OH group.

The term “oxo” as used herein, means a=O group.

The term “pain”, as used herein, is understood to mean nociceptive painand neuropathic pain, both chronic and acute pain, including but notlimited to, osteoarthritis or rheumatoid arthritis pain, ocular pain,pains associated with intestinal inflammation, pains associated withcardiac muscle inflammation, pains associated with multiple sclerosis,pains associated with neuritis, pains associated with carcinomas andsarcomas, pains associated with AIDS, pains associated withchemotherapy, amputation pain, trigeminus neuralgia, headaches, such asmigraine cephalalgia, or neuropathic pains, such as post-herpes zosterneuralgia, post-injury pains and post-operative pains.

The term “sulfonyl” as used herein, means a —SO₂— group.

b. COMPOUNDS

Compounds of the present invention have the formula (I) as describedabove. Particular values of variable groups in compounds of formula (I)are as follows. Such values may be used where appropriate with any ofthe other values, definitions, claims or embodiments definedhereinbefore or hereinafter.

In one embodiment, R¹ is selected from the group consisting of hydrogen,alkyl, alkylcarbonyl, haloalkyl, G¹, —(CR^(4a)R^(5a))_(m)G¹, —C(O)-G¹,—S(O)₂-G¹, —C(O)OR⁶ and —C(O)NR⁷R⁸; wherein R¹ is other than hydrogen,alkyl, alkylcarbonyl, or haloalkyl when one of Y¹ or Y² is CH₂ and theother is NR⁹; G¹, at each occurrence, is independently aryl orheteroaryl, wherein each G¹ is independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, alkenyl, halogen, cyano, —NO₂, —OR^(1b),—S(O)₂R^(2b), —C(O)OR^(1b), —(CR^(4a)R^(5a))_(m)—N(R^(1b))₂, andhaloalkyl; R^(4a) and R^(5a), at each occurrence, are each independentlyhydrogen, halogen, alkyl, or haloalkyl, or R^(4a) and R^(5a) togetherwith the carbon to which they are attached form a cycloalkyl; m, at eachoccurrence, is independently 1, 2, 3, 4, or 5; R⁶ is alkyl or—(CR^(4a)R^(5a))_(m)-G¹; R⁷, and R⁸ are independently hydrogen, alkyl,G¹, or —(CR^(4a)R^(5a))_(m)G¹; R⁹ is hydrogen or alkyl; R^(1b), at eachoccurrence, is independently hydrogen, alkyl, or haloalkyl; and R^(2b),at each occurrence, is independently alkyl, cyanoalkyl or haloalkyl.

In another embodiment, R¹ is hydrogen, alkyl, alkylcarbonyl, orhaloalkyl.

In a further embodiment, R¹ is hydrogen, alkyl, or alkylcarbonyl.

In another embodiment, Ri is G¹, —(CR^(4a)R^(5a))_(m)G¹, —C(O)-G¹,—S(O)₂-G¹, —C(O)OR⁶ or —C(O)NR⁷R⁸.

In another embodiment, Ri is G¹, —(CR^(4a)R^(5a))_(m)G¹, —C(O)-G¹,—S(O)₂-G¹, or —C(O)OR⁶.

In one embodiment, R², R³, and R⁴ are each independently hydrogen,alkyl, alkenyl, alkynyl, halogen, cyano, —NO₂, —OR^(1a), —S(O)₂R^(2a),—C(O)OR^(1a), or haloalkyl; wherein R^(1a), at each occurrence, isindependently hydrogen, alkyl, haloalkyl, or —(CR^(4a)R^(5a))_(m)G¹; andR^(2a), at each occurrence, is independently alkyl, haloalkyl, or G¹.

In another embodiment, R², R³, and R⁴ are each independently hydrogen,alkyl, alkenyl, alkynyl, halogen, cyano, —NO₂, —OR^(1a), or haloalkyl.

In another embodiment, R², R³, and R⁴ are each independently—S(O)₂—R^(2a) or —C(O)OR^(1a).

In a further embodiment, R², R³, and R⁴ are each hydrogen.

In one embodiment, R⁵ is hydrogen, alkyl, alkenyl, alkynyl, halogen,cyano, —NO₂, —OR^(1a), —S(O)₂R^(2a), —C(O)OR^(1a), or haloalkyl; whereinR^(1a), at each occurrence, is independently hydrogen, alkyl, haloalkyl,or —(CR^(4a)R^(5a))_(m)G¹; and R^(2a), at each occurrence, isindependently alkyl, haloalkyl, or G¹.

In another embodiment, R⁵ is hydrogen, alkyl, alkenyl, alkynyl, halogen,cyano, —NO₂, —OR^(1a), or haloalkyl.

In another embodiment, R⁵ is —S(O)₂—R^(2a) or —C(O)OR^(1a).

In a further embodiment, R⁵ is hydrogen.

In one embodiment, R^(1a), at each occurrence, is independentlyhydrogen, alkyl, haloalkyl, or —(CR^(4a)R^(5a))_(m)G¹.

In another embodiment, R^(1a) is hydrogen.

In another embodiment, R^(1a) is alkyl.

In another embodiment, R^(1a) is haloalkyl.

In another embodiment, R^(1a) is —(CR^(4a)R^(5a))_(m)-G¹.

In one embodiment, R^(2a), at each occurrence, is independently alkyl,haloalkyl, or G¹.

In another embodiment, R^(2a) is alkyl.

In another embodiment, R^(2a) is haloalkyl.

In another embodiment, R^(2a) is G¹.

In one embodiment, R^(4a) and R^(5a), at each occurrence, are eachindependently hydrogen, halogen, alkyl, or haloalkyl, or R^(4a) andR^(1a) together with the carbon to which they are attached form acycloalkyl.

In another embodiment, R^(4a) and R^(1a), at each occurrence, are eachhydrogen.

In another embodiment, R^(4a) and R^(1a), at each occurrence, are eachindependently hydrogen or alkyl.

In another embodiment, R^(4a) and R^(1a), together with the carbon towhich they are attached form a cycloalkyl.

In one embodiment, R^(1b), at each occurrence, is independentlyhydrogen, alkyl, or haloalkyl.

In another embodiment, R^(1b) is hydrogen.

In another embodiment, R^(1b) is alkyl.

In another embodiment, R^(1b) is haloalkyl.

In one embodiment, R^(2b), at each occurrence, is independently alkyl,cyanoalkyl or haloalkyl.

In another embodiment, R^(2b) is alkyl.

In another embodiment, R^(2b) is cyanoalkyl.

In another embodiment, R^(2b) is haloalkyl.

In one embodiment, G¹, at each occurrence, is independently aryl orheteroaryl, wherein each G¹ is independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, alkenyl, halogen, cyano, —NO₂, —OR^(1b),—S(O)₂—R^(2b), —C(O)OR^(1b), —(CR^(4a)R^(5a))_(m)—N(R^(1b))₂, andhaloalkyl.

In another embodiment, G¹ is aryl, wherein each G¹ is independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of alkyl, alkenyl, halogen, cyano, —NO₂,—OR^(1b), —S(O)₂R^(2b), —C(O)OR^(1b), —(CR^(4a)R^(5a))_(m)—N(R^(1b))₂,and haloalkyl.

In another embodiment, G¹ is heteroaryl, wherein each G¹ isindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, alkenyl,halogen, cyano, —NO₂, —OR^(1b), S(O)₂R^(2b), C(O)OR^(1b),—(CR^(4a)R^(5a))_(m)—N(R^(1b))₂, and haloalkyl.

In one embodiment, G², at each occurrence, is independently cycloalkylor heterocycle, wherein each G² is independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, alkenyl, halogen, cyano, —NO₂, —OR^(1b),—S(O)₂R^(2b), —C(O)OR^(1b), —C(O)R^(2b), —C(O)N(R^(1b))₂, haloalkyl, andoxo.

In another embodiment, G², at each occurrence, is cycloalkyl, whereineach G² is independently unsubstituted or substituted with 1, 2, 3, 4,or 5 substituents selected from the group consisting of alkyl, alkenyl,halogen, cyano, —NO₂, —OR^(1b), S(O)₂R^(2b), C(O)OR^(1b), —C(O)R^(2b),—C(O)N(R^(1b))₂, haloalkyl, and oxo.

In another embodiment, G², at each occurrence, is heterocycle, whereineach G² is independently unsubstituted or substituted with 1, 2, 3, 4,or 5 substituents selected from the group consisting of alkyl, alkenyl,halogen, cyano, —NO₂, —OR^(1b), —S(O)₂R^(2b), —C(O)OR^(1b), —C(O)R^(2b),—C(O)N(R^(1b))₂, haloalkyl, and oxo.

In one embodiment, m, at each occurrence is 1, 2, 3, 4, or 5.

In another embodiment, m, at each occurrence is 1, 2, or 3.

In a further embodiment, m, at each occurrence is 1 or 2.

In one embodiment, W¹ is NHC(O)G¹ or —O—(CR^(4a)R^(5a))_(m)—R^(1b).

In another embodiment, W¹ is NHC(O)G¹.

In another embodiment, W¹ is —O—(CR^(4a)R^(5a))_(m)—R^(1b).

In one embodiment, W¹ is —O—(CR^(4a)R^(5a))_(m)—R^(1b).

In another embodiment, W² is G¹.

In another embodiment, W² is G².

In another embodiment, W² is N(R^(1b))₂.

In another embodiment, W² is R^(1b).

In another embodiment, W² is —O—(CR^(4a)R^(5a))_(m)—R^(1b).

In one embodiment, X¹ is N or CR⁵.

In another embodiment, X¹ is CR⁵.

In a further embodiment, X¹ is CH.

In a further embodiment, X¹ is N.

In one embodiment, one of Y¹ or Y² is CH₂ and the other is selected fromthe group consisting of NR⁹, N-G¹, N—(CR^(4a)R^(5a))_(m)-G¹,N⁺—[(CR^(4a)R^(5a))_(m)-G¹]₂, NC(O)—R^(2b),NC(O)—(CR^(4a)R^(5a))_(m)-G¹, NC(O)—(CR^(4a)R^(5a))_(m)—W¹,NC(O)—CH═CH-G¹, NC(O)-G¹, NC(O)-G²-G¹, N-G², N-G²-C(O)-G¹,N—(CR^(4a)R^(5a))_(m)-G², NC(O)—(CR^(4a)R^(5a))_(m)-G², NC(O)-G²,NC(O)NH—W³, NC(O)N(R^(2b))—W³, and NC(O)N(Rb)-(CR^(4a)R^(5a))_(m)—W²;wherein R⁹ is hydrogen or alkyl; G¹, at each occurrence, isindependently aryl or heteroaryl, wherein each G¹ is independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of alkyl, alkenyl, halogen, cyano, —NO₂,—OR^(1b), —S(O)₂R^(2b), —C(O)OR^(1b), —(CR^(4a)R^(5a))_(m)—N(R^(1b))₂,and haloalkyl; R^(4a) and R^(5a), at each occurrence, are eachindependently hydrogen, halogen, alkyl, or haloalkyl, or R^(4a) andR^(5a) together with the carbon to which they are attached form acycloalkyl; m, at each occurrence, is independently 1, 2, 3, 4, or 5;G², at each occurrence, is independently cycloalkyl or heterocycle,wherein each G² is independently unsubstituted or substituted with 1, 2,3, 4, or 5 substituents selected from the group consisting of alkyl,alkenyl, halogen, cyano, —NO₂, —OR^(1b), —S(O)₂R^(2b), —C(O)OR^(1b),—C(O)R^(2b), —C(O)N(R^(1b))₂, haloalkyl, and oxo; R^(1b), at eachoccurrence, is independently hydrogen, alkyl, or haloalkyl; R^(2b), ateach occurrence, is independently alkyl, cyanoalkyl, or haloalkyl; W¹ isNHC(O)G¹ or —O—(CR^(4a)R^(5a))_(m)—R^(1b); W² is G¹, G², N(R^(1b))₂,R^(1b), or —O—(CR^(4a)R^(5a))_(m)—R^(1b); and W³ is R^(1b), G¹ or G².

In one embodiment, Y¹ is CH₂ and Y² is NR⁹ wherein R⁹ is hydrogen oralkyl.

In another embodiment, Y¹ is CH₂ and Y² is NR⁹ wherein R⁹ is hydrogen.

In a further embodiment, Y¹ is CH₂ and Y² is NR⁹ wherein R⁹ is alkyl.

In one embodiment, Y¹ is NR⁹, wherein R⁹ is hydrogen or alkyl, and Y² isCH₂.

In another embodiment, Y¹ is NR⁹, wherein R⁹ is hydrogen, and Y² is CH₂.

In a further embodiment, Y¹ is NR⁹, wherein R⁹ is alkyl, and Y² is CH₂.

In one embodiment, Y¹ is CH₂ and Y² is N-G¹, N—(CR^(4a)R^(5a))_(m)-G¹,N¹—[(CR^(4a)R^(5a))_(m)-G¹]₂, NC(O)—R^(2b),NC(O)—(CR^(4a)R^(5a))_(m)-G¹, NC(O)—(CR^(4a)R^(5a))_(m)—W¹,NC(O)—CH═CH-G¹, NC(O)-G¹, NC(O)-G²-G¹, N-G², N-G²-C(O)-G¹,N—(CR^(4a)R^(5a))_(m)-G², NC(O)—(CR^(4a)R^(5a))_(m)-G², NC(O)-G²,NC(O)NH—W³, NC(O)N(R^(2b))—W³, or NC(O)N(R^(1b))—(CR^(4a)R^(5a))_(m)—W².

In another embodiment, Y¹ is CH₂ and Y² is N-G¹,N—(CR^(4a)R^(5a))_(m)-G¹, N⁺—[(CR^(4a)R^(5a))_(m)-G¹]₂, NC(O)—R^(2b),NC(O)—(CR^(4a)R^(5a))_(m)-G, NC(O)—(CR^(4a)R^(5a))_(m)—W¹,NC(O)—CH═CH-G¹, NC(O)-G¹, NC(O)-G²-G¹, N-G²-C(O)-G¹, NC(O)-G²,NC(O)NH—W³, NC(O)N(R^(2b))—W³, orNC(O)N(R^(11b))—(CR^(4a)R^(5a))_(m)—W².

In another embodiment, Y¹ is CH₂ and Y² is N-G¹.

In another embodiment, Y¹ is CH₂ and Y² is N—(CR^(4a)R^(5a))_(m)-G¹,wherein R^(4a) and R^(5a), at each occurrence, are each hydrogen, orR^(4a) and R^(5a) together with the carbon to which they are attachedform a cycloalkyl, and m is 1 or 2.

In another embodiment, Y¹ is CH₂ and Y² is N⁺-[(CR^(4a)R^(5a))_(m)-G¹]₂,wherein R^(4a) and R^(5a), at each occurrence, are each hydrogen, and mis 1 or 2.

In another embodiment, Y¹ is CH₂ and Y² is NC(O)—R^(2b), wherein R^(2b)is alkyl or haloalkyl.

In another embodiment, Y¹ is CH₂ and Y² is NC(O)—(CR^(4a)R^(5a))_(m)-G¹,wherein R^(4a) and R^(5a), at each occurrence, are each hydrogen, orR^(4a) and R^(5a) together with the carbon to which they are attachedform a cycloalkyl, and m is 1 or 2.

In another embodiment, Y¹ is CH₂ and Y² is NC(O)—(CR^(4a)R^(5a))_(m)—W¹,wherein R^(4a) and R^(5a), at each occurrence, are each hydrogen, m is 1or 2, and W¹ is NHC(O)G¹ or —O —(CR^(4a)R^(5a))-m-R^(1b).

In another embodiment, Y¹ is CH₂ and Y² is NC(O)—CH═CH-G¹.

In another embodiment, Y¹ is CH₂ and Y² is NC(O)-G¹.

In another embodiment, Y¹ is CH₂ and Y² is NC(O)-G²-G¹.

In a further embodiment, Y¹ is CH₂ and Y² is NC(O)-G²-G¹, wherein G² iscyclopropyl.

In another embodiment, Y¹ is CH₂ and Y² is N-G².

In another embodiment, Y¹ is CH₂ and Y² is N-G²-C(O)-G¹.

In a further embodiment, Y¹ is CH₂ and Y² is N-G²-C(O)-G¹, wherein G² ispiperidinyl.

In another embodiment, Y¹ is CH₂ and Y² is N—(CR^(4a)R^(5a))-G².

In another embodiment, Y¹ is CH₂ and Y² is NC(O)—(CR^(4a)R^(5a))-G².

In another embodiment, Y¹ is CH₂ and Y² is NC(O)-G².

In another embodiment, Y¹ is CH₂ and Y² is NC(O)NH—W³.

In a further embodiment, Y¹ is CH₂ and Y² is NC(O)NH—W³, wherein W³ isR^(1b), G¹ or G².

In another embodiment, Y¹ is CH₂ and Y² is NC(O)N(R^(2b))—W³.

In a further embodiment, Y¹ is CH₂ and Y² is NC(O)N(R^(2b))—W³, whereinR^(2b) is alkyl, cyanoalkyl or haloalkyl and W³ is R^(1b), G¹ or G².

In another embodiment, Y¹ is CH₂ and Y² isNC(O)N(R^(1b))—(CR^(4a)R^(5a))_(m)—W².

In a further embodiment, Y¹ is CH₂ and Y² isNC(O)N(R^(1b))—(CR^(4a)R^(5a))_(m)—W², wherein R^(1b) is hydrogen,alkyl, or haloalkyl, R^(4a) and R^(5a) are each hydrogen, m is 1, and W²is G¹, G², N(R^(1b))₂, or —O—(CR^(4a)R^(5a))_(m)—R^(1b).

In another embodiment, Y¹ is N-G′, N—(CR^(4a)R^(5a))_(m)-G¹,N⁺-[(CR^(4a)R^(5a))_(m)-G¹]₂, NC(O)—R^(2b),NC(O)—(CR^(4a)R^(5a))_(m)-G¹, NC(O)—(CR^(4a)R^(5a))_(m)—WI,NC(O)—CH═CH-G¹, NC(O)-G¹, NC(O)-G²-G¹, N-G², N-G²-C(O)-G¹,N—(CR^(4a)R^(5a))_(m)-G², NC(O)—(CR^(4a)R^(5a))_(m)-G², NC(O)-G²,NC(O)NH—W³, NC(O)N(R^(2b))—W³, or NC(O)N(Rb)-(CR^(4a)R^(5a))_(m)—W² andY² is CH₂.

In another embodiment, Y¹ is N-G¹ and Y² is CH₂.

In another embodiment, Y¹ is N—(CR^(4a)R^(5a))_(m)-G¹, wherein R^(4a)and R^(5a), at each occurrence, are each hydrogen, and m is 1 or 2, andY² is CH₂.

In another embodiment, Y¹ is N⁺-[(CR^(4a)R^(5a))_(m)-G¹]₂, whereinR^(4a) and R^(5a), at each occurrence, are each hydrogen, and m is 1 or2, and Y² is CH₂.

In another embodiment, Y¹ is NC(O)—R^(2b), wherein R^(2b) is alkyl,cyanoalkyl or haloalkyl, and Y² is CH₂.

In another embodiment, Y¹ is NC(O)—(CR^(4a)R^(5a))_(m)-G¹, whereinR^(4a) and R^(5a), at each occurrence, are each hydrogen, and m is 1 or2, and Y² is CH₂.

In another embodiment, Y¹ is NC(O)—(CR^(4a)R^(5a))_(m)—W¹, whereinR^(4a) and R^(5a), at each occurrence, are each hydrogen, and m is 1 or2, W¹ is NHC(O)G¹ or —O—(CR^(4a)R^(5a))_(m)—R^(1b), and Y² is CH₂.

In another embodiment, Y¹ is NC(O)—CH═CH-G¹ and Y² is CH₂.

In another embodiment, Y¹ is NC(O)-G¹ and Y² is CH₂.

In another embodiment, Y¹ is NC(O)-G²-G¹ and Y² is CH₂.

In another embodiment, Y¹ is N-G² and Y² is CH₂.

In another embodiment, Y¹ is N-G²-C(O)-G¹ and Y² is CH₂.

In another embodiment, Y¹ is NC(O)-G² and Y² is CH₂.

In another embodiment, Y¹ is N—(CR^(4a)R^(5a))_(m)-G², wherein R^(4a)and R^(5a), at each occurrence, are each hydrogen, m is 1 or 2, and Y²is CH₂.

In another embodiment, Y¹ is NC(O)—(CR^(4a)R^(5a))_(m)-G², whereinR^(4a) and R^(5a), at each occurrence, are each hydrogen, m is 1 or 2,and Y² is CH₂.

In another embodiment, Y¹ is NC(O)NH—W³, wherein W³ is R^(1b), G¹ or G²,and Y² is CH₂.

In another embodiment, Y¹ is NC(O)N(R^(2b))—W³, wherein W³ is R^(1b), G¹or G², R^(2b) is alkyl, cyanoalkyl or haloalkyl, and Y² is CH₂.

In another embodiment, Y¹ is NC(O)N(R^(1b))—(CR^(4a)R^(5a))_(m)—W²,wherein W² is G¹, G², N(R^(1b))₂, R^(1b) or—O—(CR^(4a)R^(5a))_(m)—R^(1b), and Y² is CH₂.

In one embodiment, Y³ is CH₂ or C(O).

In another embodiment, Y³ is C(O).

In a further embodiment, Y³ is CH₂.

In one embodiment, compounds of formula (I) can include compounds offormula (Ia):

wherein R¹, R², R³, R⁴, R⁵ and Y² are as described above.

In another embodiment, compounds of formula (Ia) are disclosed whereinY² is selected from the group consisting of NR⁹,N—(CR^(4a)R^(5a))_(m)-G², or N—(CR^(4a)R^(5a))_(m)-G¹, wherein R⁹,R^(4a), R^(5a), m, G² and G¹ are as described in the Summary of theInvention.

In a further embodiment, compounds of formula (Ia) are disclosed whereinY² is selected from the group consisting of NH, N—(CR^(4a)R^(5a))_(m)-G²or N—(CR^(4a)R^(5a))_(m)-G¹, wherein R^(4a), R^(5a), m, G² and G¹ are asdescribed in the Summary of the Invention.

In one embodiment, compounds of formula (I) can include compounds offormula (Ib):

wherein R¹, R², R³, R⁴, R⁵ and Y² are as described above.

In another embodiment, compounds of formula (Ib) are disclosed whereinY² is NR⁹, N-G¹, N—(CR^(4a)R^(5a))_(m)-G¹, N⁺-[(CR^(4a)R^(5a))_(m)-G¹]₂,NC(O)—R^(2b), NC(O)—(CR^(4a)R^(5a))_(m)-G¹, NC(O)—CH═CH-G¹, NC(O)-G¹,NC(O)-G²-G¹, N-G², N-G²-C(O)-G¹, N—(CR^(4a)R^(5a))_(m)-G²,NC(O)—(CR^(4a)R^(5a))_(m)-G², NC(O)-G², NC(O)—(CR^(4a)R^(5a))_(m)—W¹,NC(O)N(R^(1b))—(CR^(4a)R^(5a))_(m)—W², or NC(O)N(R^(2b))—W³, wherein R⁹,R^(4a), R^(5a), R^(1b), R^(2b), W¹, W², W³, m, G¹ and G² are asdescribed in the Summary of the Invention.

In another embodiment, compounds of formula (Ib) are disclosed whereinY² is NR⁹, wherein R⁹ is hydrogen or alkyl.

In a further embodiment, compounds of formula (Ib) are disclosed whereinY² is N-G¹, N—(CR^(4a)R^(5a))_(m)-G¹, N¹—[(CR^(4a)R^(5a))_(m)-G¹]₂,NC(O)—R^(2b), NC(O)—(CR^(4a)R^(5a))_(m)-G¹, NC(O)—CH═CH-G¹, NC(O)-G¹,NC(O)-G²-G¹, N-G²-C(O)-G¹, N—(CR^(4a)R^(5a))_(m)-G²,NC(O)—(CR^(4a)R^(5a))_(m)-G², NC(O)-G², NC(O)—(CR^(4a)R^(5a))_(m)—W¹,NC(O)N(R^(1b))—(CR^(4a)R^(5a))_(m)—W², NC(O)N(R^(2b))—W³, whereinR^(4a), R^(5a), R^(1b), R^(2b), W¹, W², W³, m, G¹ and G² are asdescribed in the Summary of the Invention.

In one embodiment, compounds of formula (I) can include compounds offormula (Ic):

wherein R¹, R², R³, R⁴, R⁵ and Y¹ are as described above.

In another embodiment, compounds of formula (Ic) are disclosed whereinY¹ is NR⁹, N-G¹, N—(CR^(4a)R^(5a))_(m)-G¹,N⁺-[(CR^(4a)R^(5a))_(m)-G^(1]2), NC(O)—(CR^(4a)R^(5a))_(m)-G¹,NC(O)—CH═CH-G¹, NC(O)-G¹, NC(O)-G²-G¹, N-G², N—(CR^(4a)R^(5a))_(m)-G²,NC(O)—(CR^(4a)R^(5a))_(m)-G², or NC(O)-G², wherein R⁹, R^(4a), R^(5a),m, G¹ and G² are as described in the Summary of the Invention.

In another embodiment, compounds of formula (Ic) are disclosed whereinY¹ is NR⁹, wherein R⁹ is hydrogen or alkyl.

In a further embodiment, compounds of formula (Ic) are disclosed whereinY¹ is N-G¹, N—(CR^(4a)R^(5a))_(m)-G¹, N⁺-[(CR^(4a)R^(5a))_(m)-G^(1]2),NC(O)—(CR^(4a)R^(5a))_(m)-G¹, NC(O)—CH═CH-G¹, NC(O)-G¹, NC(O)-G²-G¹,N-G², N—(CR^(4a)R^(5a))_(m)-G², NC(O)—(CR^(4a)R^(5a))_(m)-G², orNC(O)-G², wherein R^(4a), R^(5a), m, G¹ and G² are as described in theSummary of the Invention.

In one embodiment, compounds of formula (I) can include compounds offormula (Id):

wherein R¹, R², R³, R⁴, and Y¹ are as described above.

In another embodiment, compounds of formula (Id) are disclosed whereinY¹ is NR⁹, N-G¹, N—(CR^(4a)R^(5a))_(m)-G¹, N⁺-[(CR^(4a)R^(5a))_(m)-G¹]₂,NC(O)—(CR^(4a)R^(5a))_(m)-G¹, NC(O)—CH═CH-G¹, NC(O)-G¹, NC(O)-G²-G¹,N-G², N—(CR^(4a)R^(5a))_(m)-G², NC(O)—(CR^(4a)R^(5a))_(m)-G², orNC(O)-G²,

wherein R⁹, R^(4a), R^(5a), m, G¹ and G² are as described in the Summaryof the Invention.

In another embodiment, compounds of formula (Id) are disclosed whereinY¹ is NR⁹, wherein R⁹ is hydrogen or alkyl.

In a further embodiment, compounds of formula (Id) are disclosed whereinY¹ is N—(CR^(4a)R^(5a))_(m)-G¹, NC(O)—(CR^(4a)R^(5a))_(m)-G¹,N—(CR^(4a)R^(5a))_(m)-G², or NC(O)-G², wherein R^(4a), R^(5a), m, G¹ andG² are as described in the Summary of the Invention.

Specific embodiments of compounds contemplated as part of the inventioninclude, but are not limited to:

-   tert-butyl    5-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate;-   3-benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-phenylethanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(phenyl)methanone;-   3,6,6-tribenzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepin-6-ium;-   3,6-dibenzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(pyrimidin-2-yl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(4-fluorophenyl)methanone;-   3-benzyl-6-(pyrazin-2-yl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(pyrazin-2-yl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1-phenylcyclopropyl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(morpholin-4-yl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)[trans-2-phenylcyclopropyl]methanone;-   3-benzyl-6-(pyridin-2-yl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   (−)-3-benzyl-6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   (+)-3-benzyl-6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   (2E)-1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-3-phenylprop-2-en-1-one;-   3-benzyl-6-[4-(trifluoromethyl)benzyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   7-(4-bromobenzyl)-3-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;-   3-benzyl-6-(4-bromo-3-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(3,5-difluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(3,4-difluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;-   1-(3-benzyl-2,3,4,4a,5,6-hexahydropyrazino[1,2-a][1,5]benzodiazepin-7(1H)-yl)-2-(4-chlorophenyl)ethanone;-   3-benzyl-6-(pyridin-3-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(pyridin-2-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(pyridin-4-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(4-bromophenyl)methanone;-   3-benzyl-6-[(6-methylpyridin-3-yl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(quinolin-3-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-[(6-chloropyridin-3-yl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(quinolin-4-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(isoquinolin-4-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-(4-fluorobenzyl)-2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one;-   3-benzyl-6-[(6-bromopyridin-3-yl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   (3-benzyl-2,3,4,4a,5,6-hexahydropyrazino[1,2-a][1,5]benzodiazepin-7(1H)-yl)(4-bromophenyl)methanone;-   3-benzyl-6-[(5-bromopyridin-2-yl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   (3-benzyl-2,3,4,4a,5,6-hexahydropyrazino[1,2-a][1,5]benzodiazepin-7(1H)-yl)(pyridin-4-yl)methanone;-   3-benzyl-7-[2-(4-chlorophenyl)ethyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;-   3,7-dibenzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;-   3-benzyl-6-(4-iodobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-7-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;-   3-benzyl-7-(pyridin-4-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;-   3-benzyl-7-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;-   4-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methyl]phenol;-   9-benzyl-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one;-   9-benzyl-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;-   1-(9-benzyl-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl)-2-(4-chlorophenyl)ethanone;-   9-benzyl-5-[2-(4-chlorophenyl)ethyl]-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;-   9-benzyl-5-methyl-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;-   6-(4-bromobenzyl)-3-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   6-(4-bromobenzyl)-3-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   (9-benzyl-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl)(2,2,3,3-tetramethylcyclopropyl)methanone;-   9-benzyl-5-[(2,2,3,3-tetramethylcyclopropyl)methyl]-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;-   1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-(6-chloropyridin-3-yl)ethanone;-   (+)-(4aS)-6-(4-bromobenzyl)-3-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;

(−)-(4aR)-6-(4-bromobenzyl)-3-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;

-   3-benzyl-6-[2-(6-chloropyridin-3-yl)ethyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   5-(cyclopropylmethyl)-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;-   5-(cyclobutylmethyl)-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;-   tert-butyl    6-(4-bromobenzyl)-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate;-   tert-butyl    6-(4-bromobenzyl)-5-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate;-   5-[(2S)-azetidin-2-ylmethyl]-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;-   5-(azetidin-3-ylmethyl)-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;-   6-(4-bromobenzyl)-2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one;-   6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   cyclopropyl(7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl)methanone;-   6-(4-bromobenzyl)-3-(4-fluorobenzyl)-2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one;-   [5-(cyclopropylmethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-9(5H)-yl](pyridin-3-yl)methanone;-   1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl(morpholin-4-yl)methanone;-   [3-(4-fluorobenzyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl](morpholin-4-yl)methanone;-   (3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(morpholin-4-yl)methanone;-   2-[2-(3-benzyl-2,3,4,4a,5,6-hexahydropyrazino[1,2-a][1,5]benzodiazepin-7(1H)-yl)-2-oxoethyl]pyridazin-3(2H)-one;-   (3-benzoyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(morpholin-4-yl)methanone;-   morpholin-4-yl[3-(pyrimidin-2-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl]methanone;-   morpholin-4-yl[3-(phenylsulfonyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl]methanone;-   [3-(4-chlorophenyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl](morpholin-4-yl)methanone;-   1-[6-(morpholin-4-ylcarbonyl)-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-3(4H)-yl]ethanone;-   1-{4-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)carbonyl]piperidin-1-yl}ethanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1H-pyrazol-4-yl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1H-pyrazol-5-yl)methanone;-   1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-(morpholin-4-yl)ethanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1,3-thiazol-4-yl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1,3-thiazol-5-yl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1,2-oxazol-5-yl)methanone;-   1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-3-(pyrrolidin-1-yl)propan-1-one;-   1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-cyclopropylethanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1H-pyrrol-2-yl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(3-furyl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1,2,5-trimethyl-1H-pyrrol-3-yl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(2,5-dimethyl-1H-pyrrol-3-yl)methanone;-   1-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)carbonyl]cyclopropanecarboxamide;-   1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-(pyridin-3-yl)ethanone;-   N-[2-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-oxoethyl]-2-furamide;-   1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-methylpropan-1-one;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(3,5-dimethyl-1,2-oxazol-4-yl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(5-methylpyrazin-2-yl)methanone;-   1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-(4-methylpiperazin-1-yl)ethanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(2-furyl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1-methyl-1H-pyrrol-2-yl)methanone;-   1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)propan-1-one;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(pyridin-4-yl)methanone;-   1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)butan-1-one;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(tetrahydrofuran-3-yl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(pyridin-3-yl)methanone;-   1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-3-(piperidin-1-yl)propan-1-one;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(cyclopropyl)methanone;-   1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-ethoxyethanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1-methylcyclopropyl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(cyclobutyl)methanone;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(2-methylcyclopropyl)methanone;-   1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-3,3,3-trifluoropropan-1-one;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(tetrahydrofuran-2-yl)methanone;-   3-benzyl-6-(4-methoxy-3-methylbenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-[(4,5-dimethyl-2-furyl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(4-ethoxybenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-[(5-methyl-2-thienyl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(2-naphthylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(cyclopentylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(quinolin-2-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-[(5-ethyl-2-furyl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   4-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methyl]benzonitrile;-   3-benzyl-6-butyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(4-chlorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(2-methylbenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(2-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(2-methoxybenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(4-methoxybenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(3-methoxybenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(3-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(4-methylbenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(1-naphthylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(2-chlorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(3-chlorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(2,2-dimethylpropyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-[(3-methyl-2-thienyl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(3-methylbutyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(cyclohexylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-(3-methylbenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methyl]benzonitrile;-   3-benzyl-6-(2-thienylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-6-isobutyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;-   3-benzyl-N-(2-methoxyethyl)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-[2-(pyridin-3-yl)ethyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-[2-(pyridin-2-yl)ethyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-[2-(pyridin-4-yl)ethyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-(2-cyanoethyl)-N-cyclopropyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   [4-(2-aminoethyl)-1H-imidazol-1-yl](3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methanone;-   3-benzyl-N-(pyridin-4-ylmethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-[(5-methyl-2-furyl)methyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-ethyl-N-(2-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N,N-diethyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-(1,3-thiazol-2-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-(cyclopropylmethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(4-isopropylpiperazin-1-yl)methanone;-   3-benzyl-N-isobutyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-(pyridin-3-ylmethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-[3-(dimethylamino)propyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-butyl-N-(cyanomethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-(3-methoxypropyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-(2-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-(pyridin-2-ylmethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-cyclobutyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   3-benzyl-N-methyl-N-propyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;-   (3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(piperidin-1-yl)methanone;-   6-(cyclopropylmethyl)-2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one;-   [4-(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)piperidin-1-yl](phenyl)methanone;-   (2-chlorophenyl)(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methanone;-   (3-chlorophenyl)(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methanone;    or-   (4-chlorophenyl)(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methanone.

Compounds of the present invention may exist as stereoisomers wherein,asymmetric or chiral centers are present. These stereoisomers are “R” or“S” depending on the configuration of substituents around the chiralcarbon atom. The terms “R” and “S” used herein are configurations asdefined in TUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., 1976, 45: 13-30.

The present application contemplates various stereoisomers and mixturesthereof and these are specifically included within the scope of thisapplication. Stereoisomers include enantiomers and diastereomers, andmixtures of enantiomers or diastereomers. Individual stereoisomers ofcompounds of the present application may be prepared synthetically fromcommercially available starting materials which contain asymmetric orchiral centers or by preparation of racemic mixtures followed byresolution which is well known to those of ordinary skill in the art.These methods of resolution are exemplified by (1) attachment of amixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of optical enantiomerson chiral chromatographic columns.

Geometric isomers may exist in the compounds of the present invention.The present invention contemplates the various geometric isomers andmixtures thereof resulting from the disposition of substituents around acarbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkylgroup, or a heterocycle group. Substituents around a carbon-carbondouble bond or a carbon-nitrogen bond are designated as being of Z or Econfiguration and substituents around a cycloalkyl or a heterocycle aredesignated as being of cis or trans configuration.

Within the present invention it is to be understood that compoundsdisclosed herein may exhibit the phenomenon of tautomerism.

Thus, the formulae drawings within this specification can represent onlyone of the possible tautomeric or stereoisomeric forms. It is to beunderstood that the present invention encompasses any tautomeric orstereoisomeric form, and mixtures thereof, and is not to be limitedmerely to any one tautomeric or stereoisomeric form utilized within thenaming of the compounds or formulae drawings.

The present invention also includes isotopically-labeled compounds,which are identical to those recited in formula (I), but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. Examples of isotopes suitable for inclusion in the compoundsof the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus,fluorine, and chlorine, such as, but not limited to ²H, ³H, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Substitutionwith heavier isotopes such as deuterium, i.e., ²H, can afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements and,hence, may be preferred in some circumstances. Compounds incorporatingpositron-emitting isotopes are useful in medical imaging andpositron-emitting tomography (PET) studies for determining thedistribution of receptors. Suitable positron-emitting isotopes that canbe incorporated in compounds of formula (I) are ¹¹C, ¹³N, ¹⁵O, and ¹⁸F.Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examplesusing appropriate isotopically-labeled reagent in place ofnon-isotopically-labeled reagent.

c. BIOLOGICAL DATA

To determine the effectiveness of compounds having a formula (I), thesecompounds can be evaluated in in vitro models of cellular function andin vivo models of pro-cognitive effects.

Abbreviations which have been used in the descriptions of BiologicalData that follow are: DMEM for Dulbecco's modified Eagle's medium; DMSOfor dimethyl sulfoxide; FBS for fetal bovine serum; FLIPR forfluorometric imaging plate reader; GFAP for glial fibrillary acidicprotein; HBSS for Hank's balanced salt solution; i.p. forintraperitoneal; NGF for nerve growth factor; PBS for phosphate bufferedsaline; and TRTTC for tetramethylrhodamine isothiocyanate.

(i) Effects on Neurite Outgrowth in Neurons and Neuronal Cell Lines:

Effects on cellular properties such as neurite outgrowth and neuronal orneuronal-like cell number, etc. can be measured either using rat orhuman neuronal/neuroblastoma cell lines (e.g., SH-SY5Y, PC12, IMR-32,etc.) or using primary cells (e.g., rat cortical neurons).

For example, studies can be conducted using PC12 cells plated in 96-wellplates, treated with or without nerve growth factor (100 ng/mL) for 6days. Compounds are then added at various concentrations (ranging from0.1 nM to 30 M), and incubated for 24 hours. Cells are then fixed andstained by neuron marker β-tubulin (green), and nuclei were stained byHoechst 33342 (blue). Images are collected using the ImageXpress Microautomatic fluorescent microscopy system (Molecular Devices, Sunnyvale,Calif.) employing a Nikon 10× Plan Fluor objective and Cool Snap HQ CCDcamera. The Neurite Outgrowth module in the MetaMorph Imaging softwarecan be used to automatically count neuron-like number, and the extent ofneurite outgrowth.

In addition to PC12 cells, other cellular model systems may also beused. Rat cortical cells can be cultured and prepared for high contentmicroscopy analysis as previously described (Hu, M.; Schurdak, M. E.; etal. High content screen microscopy analysis of Aβ₁₋₄₂-induced neuriteoutgrowth reduction in rat primary cortical neurons: Neuroprotectiveeffects of α7 neuronal nicotinic acetylcholine receptor ligands. BrainRes. 2007, 1151, 227-235.). Briefly, cortical cell cultures are platedat density of 5×10⁵ cells/mL onto poly-D-lysine coated 96-well platesand maintained in a cell incubator at 37° C. with 5% CO₂. Experimentsare performed using 6-7 day-old cortical cell cultures by treating withtest compounds. In some experiments, the effect of test compounds onreversing Aβ toxicity can also be measured (Hu, M.; Schurdak, M. E.; etal. High content screen microscopy analysis of Aβ₁₋₄₂-induced neuriteoutgrowth reduction in rat primary cortical neurons: Neuroprotectiveeffects of α7 neuronal nicotinic acetylcholine receptor ligands. BrainRes. 2007, 1151, 227-235.). For assessment of neuroprotective effects,cells are first pretreated with test compounds for about 5 hours. Mediumis then replaced with the medium containing freshly prepared about 5 μMAβ₁₋₄₂ peptide in the absence or presence of the test compounds for 3days. The untreated group contains the same percentage of vehicle (DMSO)as in the treatment groups. Cells are fixed with approximately 4%paraformaldehyde containing 0.5% Hoechst 33342 for about 15 minutes,followed by three washes using PBS (pH 7.4) and blocked with 10% donkeyserum in PBS for 1 hour at room temperature. The cells are thenincubated overnight at about 4° C. with mouse anti-tubulin monoclonalantibody (1:100) for staining neurons and rabbit anti-GFAP (1:1000) forstaining glia. In the next day, cells are incubated with FITC-labeledanti-mouse and TRITC-labeled anti-rabbit antibodies (1:1000) for about 1hour at room temperature. After fixing and staining the cells, nuclei(360/400 nm excitation and 465/300 nm emission filters), neuron (475/350nm excitation and 535/400 nm emission filters) and glial cell (535 nmexcitation and 610 nm emission filters) images are collected using theImageExpress Micro automatic fluorescent microscopy system (MolecularDevices, Sunnyvale, Calif.) employing a Nikon 10× Plan Fluor objectiveand Cool Snap HQ CCD camera. The Neurite Outgrowth module in theMetaMorph Imaging software can be used to automatically count total cellnumber, number of neuron cells, and the extent of neurite outgrowth.

(Ii) Effects on Aβ₁₋₄₂ Induced Tau Phosphorylation in PC12 Cells

The effect of test compound(s) on Aβ₁₋₄₂ induced tau phosphorylation canbe assessed in a cell line such as PC12 as previously described (Hu, M.;Waring, J. F.; et al. Role of GSK-3β activation and α7 nAChRs inAβ₁₋₄₂-induced tau phosphorylation in PC12 cells. J. Neurochem. 2008,106(3), 1371-1377.). Briefly, PC12 cells are plated on poly-D-lysinecoated 96-well plates, cultured in Ham's F12K medium supplemented with15% horse serum, 2.5% FBS, 2 mM L-glutamine, 100 U/mL penicillin and 100μg/mL streptomycin at 37° C. with 5% CO₂ and differentiated with 100ng/mL NGF for approximately 6 days. Cells are pretreated with testcompounds for 30 minutes at about 37° C. The medium is then replacedwith that containing freshly prepared Aβ₁₋₄₂ or control peptide in theabsence or presence of the test compounds and the cells are incubated at37° C. for 24 hours. Cells are fixed with 3.7% formaldehyde in PBS (pH7.4) for about 1 hour at room temperature followed by permeabilizationby three washes with 0.1% Triton-X 100 in PBS. The fixed cells areincubated with blocking buffer for about 2 hours at room temperaturefollowed by overnight incubation with primary antibodies AT8 (forphosphorylated tau), anti-human tau (for total Tau), or anti-GSK-33. Onthe next day, cells are washed 3 times with 0.1% Tween-20 in PBS, thenincubated with IRDye® 800CW anti-mouse IgG antibodies (1:100) for 1 hourat room temperature for detection of phosphorylated tau (p-tau) orGSK-313, or with the Alexa Fluor® 680 anti-rabbit antibodies (1:100) fordetection of total tau (t-tau). Cells are then washed three times, andthe target signals are simultaneously visualized using Odyssey InfraredImaging Scanner with the 680-nm fluorophore emitting an image of redcolor and the 800-nm fluorophore emitting an image of green color. Theintegrated fluorescence intensities are calculated and analyzed usingthe Odyssey Infrared Imaging System Application Software version 1.2.15(Li-Cor Biosciences (Lincoln, NB). The p-tau and t-tau levels aretypically presented as the ratio p-tau/t-tau (Hu, M.; Waring, J. F.; etal. Role of GSK-33 activation and α7 nAChRs in Aβ₁₋₄₂-induced tauphosphorylation in PC12 cells. J. Neurochem. 2008, 106(3), 1371-1377.).

(Iii) Effects on Mitochondrial Function

The method also involves a high-throughput assay using serum-deprivationconditions involving neuronal cells to screen for compounds thatincrease or preserve mitochondrial membrane potential. Such compoundscan be found to aid in rescuing cells from energy-depletion that occursin several neurodegenerative states. Mitochondrial-mediated apoptosisoccurs in response to a wide range of apoptotic stimuli including p⁵³,c-myc, DNA damage, prooxidants, chemotherapeutic agents, serumstarvation and death receptor activation (Lin C—H., Lu Y-Z., Cheng,F-C., Chu L-F. and Hsuch C-M. Bax-regulated mitochondrial-mediatedapoptosis is responsible for the in vitro ischemia induced neuronal celldeath of Sprague Dawley rat. Neuroscience Lett. 2005, 387, 22-27).

Serum deprivation for 16-18 hours initiates the early stages ofapoptosis (Chavier D, Lecoeur H, Langonne A, Borgne-Sanchez A, MarianiJ., Martinou J-C, Rebouillat D and Jacotot E. Upstream control ofapoptosis by caspase-2 in serum-deprived neurons. Apoptosis10:1243-1259, 2005) and induces stress on a cell before full commitmentto cell death. Mitochondria play a critical role in the cell forsurvival or death due to their regulation of both energy metabolism aswell as apoptosis (Sullivan P G, Rabchevsky A G, Waldmeirer P C andSpringer J E. Mitochondrial Permeability Transition in CNS Trauma: Causeor Effect of Neuronal Cell Death. J. Neuroscience Res. 2005, 79,231-239). One of the first major events to occur in apoptosis is thebreakdown of the membranes of the mitochondria to release cytochrome c,activate caspases, change electron transport and cause a decrease inmitochondrial membrane potential (Δψ_(m)). A change in Δψ_(m) thereforeserves as a measure of mitochondrial function and indicator of cellhealth.

Thus, this stress inducer, serum deprivation, combined with monitoringchanges in the mitochondrial membrane potential in a 96-well formatallows for the establishment of an efficient high-throughput screen(HTS) in order to evaluate the ability of compounds to increasemitochondrial membrane potential in the presence of stress and preservehealth of the cell. Exemplary procedures for conducting suchhigh-throughput assay are provided below.

Tissue Culture:

SK-N-SH human neuroblastoma cells obtained from American Type CultureCollection (Rockville, Md.) were maintained in the log phase of growthin Minimal Essential Media (MEM), 10% heat inactivated fetal calf serumand 100 units/mL antibiotic-antimycotic (AA). Cells were cultured andmaintained in a humidified incubator at 37° C. under 5% CO₂ and 95% air.Cells were trypsinized (0.25%) and subcultured every 3 days and usedfrom 15-18 passages. All cell culture supplies were obtained fromInvitrogen (Carlsbad, Calif.).

Serum Deprivation/JC-1 Mitochondrial Membrane Potential (MMP) Assay.

SK-N-SH cells were plated 2-3 days in advance at a concentration of50,000 cells/well onto collagen coated black-walled 96 well plates(Becton-Dickinson, Bedford, Mass.) in a total volume of 200 L. On day ofexperimental treatment, the media containing serum was aspirated fromeach well and rinsed once with MEM/1% AA without serum. The cells thenwere incubated overnight in 100 μL of MEM/1% AA (no serum) with andwithout dimebolin or novel chemical entities overnight for ˜18 hours.The following day, JC-1 dye(5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanide) wasdiluted 1:10 into MEM media according to the JC-1 Mitochondrial MembranePotential Assay Kit: (Cayman Chemical Company, Ann Arbor, Mich.) andthen 10 μL of the JC-1 dye solution was added to each well. The plateswere centrifuged for 5 minutes at 400×g at room temperature followed by40 minute incubation at 37° C. The plates were washed twice with 200 μLof provided Assay Buffer followed an addition of 100 μL of Assay Bufferto each well. The plates were read with an excitation and emission of560 nM and 595 nM for red fluorescence and with an excitation andemission of 485 nM and 535 nM for green fluorescence to determine thefinal JC-1 value taking the red to green fluorescence ratio. This assayis based on change in mitochondrial membrane potential (MMP) using thislipophilic cationic dye, JC-1, by monitoring the changes in the ratio ofred to green fluorescence as the MMP depolarizes. This change in MMPreflects the health of the cell with healthy, viable cells have a highJC-1 ratio and high MMP whereas apoptotic, unhealthy cells have a lowJC-1 ratio or low MMP.

For the ability of compounds to reverse the stress due to serumdeprivation and increase the JC-1 ratio, the percent maximal intensityin JC-1 ratio was normalized to that induced by the peak value for 10 μMdimebolin and plotted against the compound concentration to calculateEC₅₀ values and to control for plate-to-plate variability.Concentration-response data were analyzed using GraphPad Prism (SanDiego, Calif.); the EC50 values were derived from a single curve fit tothe mean data of n=2-3, in duplicates. Selected data is shown in Table1.

For the ability of other compounds to reverse the stress due to serumdeprivation and increase the JC-1 ratio, the percent maximal intensityat a single dose, 3 μM, in JC-1 ratio was normalized to that induced bythe peak value for 10 μM dimebolin (n=2-4). Data is shown in Table 2

All compounds were dissolved in dimethyl sulfoxide at 10 mM stocksolutions and tested at a concentration that the dimethyl sulfoxidelevels never exceeded 1%.

TABLE 1 JC-1 Mitochondrial Membrane Potential (MMP) Assay: EC₅₀ andMaximal JC-1 Ratio for Selected Compounds. EC₅₀ JC-1 Example (μM) max %1 9.59 88 2 3.44 186 3 2.88 226 4 2.42 263 5 6.7 57 6 6.44 148 7 >30 248 3.03 204 9 2.59 158 10 2.74 248 11 5.61 122 12 1.11 198 13 4.18 175 140.754 203 15 2.19 225 16 3.63 131 17 4.48 183 18 2.72 178 19 1.56 169 205.47 133 21 6.11 168 22 2.95 173 23 5.72 238 24 4.77 166 25 15.7 128 263.47 210 27 4.44 149 28 9.59 88 29 4.87 221 30 3.6 216 31 1.97 218 321.98 140 33 1.3 192 34 2.94 213 35 2.86 159 36 1.05 137 37 1.21 17238 >30 27 39 3.69 200 40 11.8 224 41 4.67 186 42 3.09 189 43 6.76 115 443 291 45 5.93 238 46 1.87 192 47 2.78 273 48 1.84 125 49 10.4 128 505.95 240 51 8.83 68 52 5.97 100 53 9.88 210 54 3.59 177 55 9.95 99 565.17 161 57 10.2 167 58 3.65 215 59 3.4 306 60 4.14 224 61 2.57 213 623.65 161 63 1.95 173 64 5.66 139 65 4.59 133 66 4.84 192 67 5.06 215 688.64 157 69 10.3 154 70 9.61 156 71 7.85 105 72 13.3 98 73 4.27 229 747.82 109 75 >10 48 76 7.06 127 77 10.2 57 78 8.55 143 79 9.25 86 80 11.997 81 9.92 129 82 5.11 127 83 >31.6 34 86 3.14 218 89 1.83 140 92 2.47174 93 1.56 185 94 2.76 172 95 0.282 189 96 0.856 180 99 3.15 165 1052.52 197 107 5.66 192 108 3.12 162 112 4.67 139 114 4.36 201 115 1.25177 119 3.95 172 121 4.21 167 122 3.4 133 123 3.44 186 124 3.49 193 1254.26 98 126 1.89 150 128 4.25 168 130 4 181 131 3.22 144 132 3.33 192133 3.64 163 134 3.53 163 135 4.19 154 136 2.2 172 137 3.3 143 138 1.83203 139 3.18 145 140 3.6 189 144 3.63 132 145 3.14 151 146 2.2 182 1511.8 163 152 3.08 239 156 2.4 152 158 1.02 181 160 0.645 245 161 3.18 218166 0.765 181 169 0.816 173 171 2.45 251

TABLE 2 JC-1 Mitochondrial Membrane Potential (MMP) Assay: JC-1 Ratio at3 μM for Selected Compounds. JC-1 max % Example (@ 3 μM) 84 183 85 80 8783 88 139 90 114 91 78 97 32 98 107 100 118 101 149 102 110 103 42 104178 106 81 109 65 110 97 111 162 113 51 116 198 117 70 118 84 120 −5 12726 129 40 141 12 142 13 143 30 147 1.7 148 38 149 218 150 212 153 68 15449 155 75 157 264 159 64 162 194 163 183 164 93 165 251 167 63 168 259170 273 172 0 173 68 174 41 175 40 176 40

(iv) In Vivo Models of Precognitive Effects

A range of animal models capturing diverse cognitive domains may beutilized for assessing procognitive effects of compounds. Examples ofthese models are provided in Bitner et al., (Bitner, R. S.; Bunnelle, W.H.; et al. Broad-spectrum efficacy across cognitive domains by α7nicotinic acetylcholine receptor agonism correlates with activation ofERK1/2 and CREB phosphorylation pathways. J. Neurosci. 2007, 27(39),10578-10587.). Various transgenic animal models that are relevant ofneurodegenerative diseases of interest may also be utilized to assesseffects of test compounds (Goetz, J.; Ittner, L. M. Animal models ofAlzheimer's disease and frontotemporal dementia. Nat. Rev. Neurosci.2008, 9(7), 532-544.).

Inhibitory Avoidance in Mouse: The inhibitory avoidance task involvesthe uses of a two-compartment step through apparatus (Ugo Basile,Collegeville, Pa.) that measures the animal's ability to remember abrief noxious stimulus (foot shock), and is considered a measure oftrial learning, and memory consolidation. Briefly, mice were placed in alighted compartment of the apparatus where the latency to enter into thepreferred dark compartment is recorded. Entry into a dark compartmentresults in the immediate delivery of a mild foot shock (0.2 mA, 1-secondduration). Retention testing is conducted 24 hours later with the animalagain placed in the lighted compartment where its latency to reenter thedark side of the apparatus is measured (no shock). Increasing retentionlatency is regarded as an index of memory consolidation (Bitner, R. S.;Bunnelle, W. H.; et al. Broad-spectrum efficacy across cognitive domainsby a7 nicotinic acetylcholine receptor agonism correlates withactivation of ERK1/2 and CREB phosphorylation pathways. J. Neurosci.2007, 27(39), 10578-10587.).

Social Recognition in Rat: The social recognition test measuresshort-term memory on the basis of olfactory cues, and depends on thehippocampus. Adult (350-450 g) rats are allowed to interact with ajuvenile (60-80 g) rat for a 5 minute interaction trial (T1) in whichthe adult exhibits behaviors that included close following, groomingand/or sniffing of the juvenile for as much as 40-50% of the trialduration. The juvenile rat is then removed and the adult rat immediatelyadministered various doses of test compound. A second 5 minuterecognition trial (T2) is conducted 120 minutes later where interactivebehavior of the adult rat is again monitored. If recognition memory islost over the 120 minute interval between trials, the interactivebehavior would be similar for the two trials; however, if memory isretained, the recognition ratio (T2:T1) would decline, i.e. deceasingT2:T1 ratio is regarded as an index of improved short-term recognitionmemory (Bitner, R. S.; Bunnelle, W. H.; et al. Broad-spectrum efficacyacross cognitive domains by α7 nicotinic acetylcholine receptor agonismcorrelates with activation of ERK1/2 and CREB phosphorylation pathways.J. Neurosci. 2007, 27(39), 10578-10587. Timmermann, D. B.; Groenlien, J.H.; et al. An allosteric modulator of the c7 nicotinic acetylcholinereceptor possessing cognition-enhancing properties in vivo. J.Pharmacol. Exp. Ther. 2007, 323(1), 294-307.).

Delayed Matching-to-Sample (DMTS) Titration in Monkey: Studies can beconducted in Rhesus monkeys that were initially trained in the DMTSprocedure (Buccafusco, J. J.; Terry, A. V.; et al. Profile of nicotinicacetylcholine receptor agonists ABT-594 and A-582941, with differentialsubtype selectivity, on delayed matching accuracy by young monkeys.Biochem. Pharmacol. 2007, 74(8), 1202-1211.). Using a touch-sensitivescreen in the animals home-cage, trial initiation consists ofpresentation of one of three colored stimuli (red, blue, or yellowrectangles) that remain in view (sample stimuli) until touched bysubject. Following a delay interval, two choice rectangles arepresented, one being the previous sample stimulus, in which correct(matching) choice-touch to the sample stimuli is food reinforced. Forstandard DMTS testing, the duration for each delay interval is adjustedfor each subject until three levels of performance accuracy wereapproximated: zero delay (85-100% of trials answered correctly); shortdelay interval (75-84% correct); medium delay interval (65-74% correct);and long delay interval (55-64% correct). The titration version of theDMTS task used in the present studies requires the animals to perform a96 trial session that begins with a 0 sec delay interval. If the trialis answered correctly, a 1 second delay interval is presented during thenext trial presented. The 1 second incremental progression is maintaineduntil the subject made an incorrect match. The delay interval for thetrial after an incorrect match is always decreased by 1 second. After anincorrect match, if the next trial is answered correctly, then thesubsequent trial presented a delay interval 1 second longer in duration.Dependent variables include the overall % of trials answered correctly,the number of trials to reach the maximal delay interval attained, andthe maximum and average delay interval attained (in seconds). Compoundsare administered prior to DMTS testing.

(v) Determination of Analgesic Effect Against Neuropathic Pain

Animals were prepared for testing, by use of a surgical procedure thatinduces neuropathic pain in one paw. Male Sprague Dawley rats werepurchased from Charles River (Portage, Mich.). Prior to surgery, animalswere housed in groups and maintained in a temperature-regulatedenvironment. Following nerve ligation surgery, animals were housed ingroups, and had access to food and water ad libitum.

The L5 and L6 spinal nerves of anesthetized rats were tightly ligated ina manner described previously (see Kim and Chung, Pain (1992) vol. 50pp. 355-363). An incision was made on the dorsal portion of the hip andthe muscle was blunt-dissected to reveal the spinal processes. The L6transverse process was removed, and the left side L5 and L6 spinalnerves were tightly ligated with 5.0 braided silk suture. The wound wascleaned, the membrane sewn with 4.0 dissolvable Vicryl suture and theskin closed with wound clips. The paw affected by the surgical procedure(the left paw) develops an allodynic response, a hypersensitivity tomechanical and other stimuli; neuropathic pain is assessed as anincreased sensitivity in the surgically affected (left) allodynic pawcompared to the control paw on the right side, and measured by comparingthe response of the (left side) allodynic paw to the response of theunaffected right side control paw.

For the assessment of neuropathic pain, mechanical allodynia in theaffected paw of animals that had undergone spinal nerve ligation wasevaluated using testing with von Frey filaments. As described previouslyby S. R. Chaplan, et al (“Quantitative assessment of tactile allodyniain the rat paw” J. Neurosci. Meth. (1994) vol. 53 pp. 55-63), two weeksfollowing surgery rats were acclimated to a testing box constructed ofplexiglass with a wire mesh floor which allowed access to the plantarsurface of the animal's hindpaws. Using an Up-Down method (Dixon, AnnualRev. Pharmacol. Toxicol. (1980) vol. 20, pp. 441-462; Chaplan et al.“Quantitative assessment of tactile allodynia in the rat paw” J.Neuroscience Methods (1994) vol. 53 pp. 55-63), von Frey filaments ofincreasing stiffness were applied to the plantar surface of the hindpawsand the withdrawal response of the animals was observed; for thesurgically affected paw with neuropathic pain (the left side paw) thebaseline level of allodynia has a withdrawal threshold of <4 g ofpressure. By comparison, for the control paw without allodynia (in thiscase the right side paw), the typical withdrawal pressure is around 15g. Representative compounds of the invention, administeredintraperitoneally 30 minutes before testing, are able to reduce thesymptoms of neuropathic pain and induce a dose-dependent increase in thewithdrawal threshold for allodynic (left side) limb, up to a maximumeffect of 15 g. The efficacy of the compound in reducing neuropathicpain at different doses is determined by comparing response in thesurgery-affected paw versus the response in the control paw. This isexpressed as the MPE (maximum potential effect).

(vi) Animal Pharmacokinetics

The pharmacokinetic properties of test compounds can be assessed inmouse, rat, dog and monkey to obtain various parameters includingclearance (Clp), volume of distribution and bioavailability. For thedetermination of plasma and brain concentrations of the parent compound,naïve rats or mice can be dosed with the compounds i.p. and sacrificedat various time points post-dosing. For the determination of plasmaconcentrations, blood is collected into heparinized tubes and thencentrifuged, and the separated plasma is frozen at −20° C. untilanalysis. For analysis, compounds are extracted from the samples vialiquid-liquid extraction and quantified by liquid chromatography/massspectroscopy.

d. METHODS OF USING THE COMPOUNDS

In still yet another embodiment, the present invention provides a methodfor preventing or treating a disease condition in a subject in need oftreatment thereof. The subject in need of treatment thereof can be amammal, such as, but not limited to, a human.

In one aspect, the disease condition is a neurodegeneration disorder. Aneurodegeneration disorder refers to a type of neurological diseasemarked by the loss of nerve cells in the brain or central nervoussystem. Examples of neurodegeneration disorders include, but are notlimited to, Alzheimer's disease (AD), mild cognitive impairment (MCI),age-associated memory impairment (AAMI), multiple sclerosis, Parkinson'sdisease, vascular dementia, senile dementia, AIDS dementia, Pick'sdisease, dementia caused by cerebrovascular disorders, corticobasaldegeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease,diminished CNS function associated with traumatic brain injury or anycombinations thereof.

In another aspect, the disease condition is a neuropsychiatric disorder.A neuropsychiatric disorder is a behavioral or psychological problemassociated with a known neurological condition, and typically defined asa cluster of symptoms that co-exist. Examples of neuropsychiatricdisorders include, but are not limited to, schizophrenia, cognitivedeficits in schizophrenia, attention deficit disorder, attention deficithyperactivity disorder, bipolar and manic disorders, depression or anycombinations thereof.

In a further aspect, the present invention relates to methods ofpreventing or treating a pain including neuropathic and nociceptivepain, chronic or acute, such as, without limitation, allodynia,inflammatory pain, inflammatory hyperalgesia, post herpetic neuralgia,neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy,nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns,back pain, ocular pain, visceral pain, cancer pain, dental pain,headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis,sciatica, pelvic hypersensitivity, pelvic pain, post operative pain,post stroke pain, and menstrual pain.

Cognitive deficits are recognized in various forms of neurodegenerationand neuropsychiatric disorders (such as, but not limited to, dementia,including Alzheimer's disease, (AD) and neuropsychiatric diseases,particularly schizophrenia and bipolar disorders). For example, in AD,current therapies offer modest efficacy, and therefore, there is needfor an agent that offers a superior clinical benefit. One such agent,dimebolin, has been shown to inhibit neuronal death in models ofneurodegenerative diseases suggestive of modification of diseaseprocesses (Lermontova, N. N.; Lukoyanov, N. V.; et al. Dimebon improveslearning in animals with experimental Alzheimer's disease. Bull. Exp.Biol. Med. 2000, 129(6), 544-546. Bachurin, S.; Bukatina, E.; et al.Antihistamine agent dimebon as a novel neuroprotector and a cognitionenhancer. Ann. N.Y. Acad. Sci. 2001, 939 (Neuroprotective Agents),425-435.) and more recently, shown to possess beneficial effect incognition in patients with Alzheimer's disease (Burns, A.; Jacoby, R.Dimebon in Alzheimer's disease: old drug for new indication. Lancet2008, 372(9634), 179-80. Doody, R. S.; Gavrilova, S. I.; et al. Effectof dimebon on cognition, activities of daily living, behaviour, andglobal function in patients with mild-to-moderate Alzheimer's disease: arandomised, double-blind, placebo-controlled study. Lancet 2008,372(9634), 207-215.). Patients with mild-to-moderate Alzheimer's diseaseadministered with 20 mg three times a day (60 mg/day) showed significantimprovement in the clinical course of disease, as reflected inimprovement over baseline for ADAS-Cog (Alzheimer's disease assessmentscale—cognitive subscale) (Cummings, J.; Doody, R.; Gavrilova, S.; Sano,M.; Aisen, P.; Seely, L.; Hung, D. 18-month data from an open-labelextension of a one-year controlled trial of dimebon in patients withmild-to-moderate Alzheimer's disease. Presented at the InternationalConference on Alzheimer's Disease (ICAD), Chicago, Ill., USA, July 2008;paper P4-334). Patients with mild-to-moderate Alzheimer's disease whohad earlier received the drug for 12 months had preservation of functionclose to their starting baseline on key symptoms of Alzheimer's diseaseindicated the ability of dimebolin to alter disease progression.Patients originally on placebo who received dimebolin in the extensionstudy showed stabilization across all key measures.

Beneficial effects of agents such as dimebolin have been linked todiverse mechanisms of action including effects at the level ofmitochondria. In particular, dimebolin has been reported to improveneuronal function by enhancing neuronal outgrowth and affectingmitochondrial function. For example, Hung and coworkers (Hung, D.Dimebon: A phase 3 investigational agent for Alzheimer's disease with anovel mitochondrial mechanism of action. Presented at the InternationalConference on Alzheimer's Disease, Chicago, Ill., USA, July 2008; paperS4-04-05.) reported that dimebolin can protect cells from excitotoxicdamage and improve neurite outgrowth in in vitro model systems. Othermechanisms of action may also contribute to its beneficial effects ofcompounds with a “dimebolin-like” profile. Indeed, multi-targetedmechanisms have been proposed as viable approaches for treatment ofdiverse neurodegenerative diseases (Zhang, H.-Y.One-compound-multiple-targets strategy to combat Alzheimer's disease.FEBS Lett. 2005, 579, 5260-5264. Youdim, M.; Buccafusco, J.Multi-functional drugs for various CNS targets in the treatment ofneurodegenerative disorders. Trends in Pharm. Sci. 2005, 26(1), 27-35.Csermely, P.; Agoston, V.; Pongor, S. The efficiency of multi-targetdrugs: the network approach might help drug design. Trends in Pharm.Sci. 2005, 26(4), 178-182. Cavalli, A.; Bolognesi, M. L.; Minarini, A.;Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-targetdirected ligands to combat neurodegenerative diseases. J. Med. Chem.2008, 51(3), 347-372.). Dimebolin is also thought to exert its cognitiveenhancing effects also through inhibition of butyryl-cholinesterase,acetyl cholinesterase, NMDA receptor or L-type calcium channels(Bachurin, S.; Bukatina, E.; et al. Antihistamine agent dimebon as anovel neuroprotector and a cognition enhancer. Ann. N.Y. Acad. Sci.2001, 939 (Neuroprotective Agents), 425-435. Lermontova, N. N.;Redkozubov, A. E.; et al. Dimebon and tacrine inhibit neurotoxic actionof beta-amyloid in culture and block L-type Ca(2+) channels. Bull. Exp.Biol. Med. 2001, 132(5), 1079-1083. Grigor'ev, V. V.; Dranyi, O. A.; etal. Comparative Study of Action Mechanisms of Dimebon and Memantine onAMPA- and NMDA-Subtypes Glutamate Receptors in Rat Cerebral Neurons.Bull. Exp. Biol. Med. 2003, 136(5): 474-477.). Interactions at the levelof select 5HT receptors have also been implicated in the beneficialcognitive of dimebolin-like analogs (Tkachenko, S. Discovery and in vivoevaluation of potent 5-HT6 receptor antagonists for cognitionenhancement in treating Alzheimer's disease. Presented at theInternational Conference on Alzheimer's Disease (ICAD), Chicago, Ill.,USA, July 2008; paper P2-478.). Thus, available preclinical and clinicaldata suggests that compounds exhibiting a “dimebolin-like” profile canbe beneficial in treating neurodegenerative diseases such as Alzheimer'sdisease and other dementias. Therefore, it is believed that thecompounds of the present invention exhibit at least one of themechanisms of action exhibited by dimebolin.

For treating a neurodegenerative or a neuropsychiatric disorder, themethod comprises administering to the subject in need of treatmentthereof (e.g., a mammal, such as a human) a therapeutically effectiveamount of any of the compounds as described herein, or apharmaceutically acceptable salt thereof. Alternatively, the methodcomprises administering to the subject a therapeutically effectiveamount of any of the compounds as described herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of at least one cognitive enhancingdrug. A “cognitive enhancing drug”, as defined herein, is a drug thatimproves impaired human cognitive abilities of the brain (namely,thinking, learning, and memory). Cognitive enhancing drugs work byaltering the availability of neurochemicals (e.g., neurotransmitters,enzymes, and hormones), by improving oxygen supply, by stimulating nervegrowth, or by inhibiting nerve damage. Examples of cognitive enhancingdrugs include a compound that increases the activity of acetylcholinesuch as, but not limited to, an acetylcholine receptor agonist (e.g., anicotinic α-7 receptor agonist or allosteric modulator, an α4β32nicotinic receptor agonist or allosteric modulators), anacetylcholinesterase inhibitor (e.g., donepezil, rivastigmine, andgalantamine), a butyrylcholinesterase inhibitor, an N-methyl-D-aspartate(NMDA) receptor antagonist (e.g., memantine), an activity-dependentneuroprotective protein (ADNP) agonist, a serotonin 5-HT1A receptoragonist (e.g., xaliproden), a 5-HT₄ receptor agonist, a 5-HT₆ receptorantagonist, a serotonin 1A receptor antagonist, a histamine H₃ receptorantagonist, a calpain inhibitor, a vascular endothelial growth factor(VEGF) protein or agonist, a trophic growth factor, an anti-apoptoticcompound, an AMPA-type glutamate receptor activator, a L-type or N-typecalcium channel blocker or modulator, a potassium channel blocker, ahypoxia inducible factor (HIF) activator, a HIF prolyl 4-hydroxylaseinhibitor, an anti-inflammatory agent, an inhibitor of amyloid Aβpeptide or amyloid plaque, an inhibitor of tau hyperphosphorylation, aphosphodiesterase 5 inhibitor (e.g., tadalafil, sildenafil), aphosphodiesterase 4 inhibitor, a monoamine oxidase inhibitor, orpharmaceutically acceptable salt thereof. Specific examples of suchcognitive enhancing drugs include, but are not limited to,cholinesterase inhibitors such as donepezil (Aricept®), rivastigmine(Exelon®), galanthamine (Reminyl®), N-methyl-D-aspartate antagonistssuch as memantine (Namenda®). At least one cognitive enhancing drug canbe administered simultaneously with the compounds of the presentinvention or sequentially with the compounds of the present invention(and in any order). Additionally, it is believed that the combinationsdescribed herein may have additive or synergistic effects when used inthe above-described treatment.

In still yet another embodiment, the present invention relates to amethod for preventing (the development of) a disease condition, such asa neurodegeneration disorder or a neuropsychiatric disorder. As usedherein, the term “prevent” a disease condition, such as aneurodegenerative disorder or a neuropsychiatric disorder byadministration of any of the compounds described herein means that thedetectable physical characteristics or symptoms of the disease orcondition do not develop following the administration of the compounddescribed herein. Specifically, the method of the present inventioncomprises administering to the subject in need of treatment thereof(e.g., a mammal, such as a human) a therapeutically effective amount ofany of the compounds as described herein, or a pharmaceuticallyacceptable salt thereof. Alternatively, the method comprisesadministering to the subject a therapeutically effective amount of anyof the compounds as described herein, or a pharmaceutically acceptablesalt thereof, in combination with a therapeutically effective amount ofat least one cognitive enhancing drug.

In still yet another embodiment, the present invention relates to amethod for preventing the progression (e.g., worsening) of a diseasecondition, such as a neurodegeneration disorder or a neuropsychiatricdisorder. The method comprises administering to the subject in need oftreatment thereof (e.g., a mammal, such as a human) a therapeuticallyeffective amount of any of the compounds as described herein, or apharmaceutically acceptable salt thereof. Alternatively, the methodcomprises administering to the subject a therapeutically effectiveamount of any of the compounds as described herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of at least one cognitive enhancingdrug.

In the above described methods for preventing the development orprogression of a neurodegeneration disorder or a neuropsychiatricdisorder one or more biomarkers, diagnostic tests or combination ofbiomarkers and diagnostic tests known to those skilled the art can beused to determine whether or not (1) a subject is at risk of developingone or more of neurodegeneration disorders or neuropsychiatricdisorders; or (2) the neurodegeneration disorders or neuropsychiatricdisorders in the subject previously diagnosed with one or more of theaforementioned disorders is progressing (e.g., worsening).

One or more biomarkers, diagnostic tests or combinations of biomarkersand diagnostic tests known in the art can be used to identify subjectswho are at risk of developing a neurodegeneration disorder or aneuropsychiatric disorder. Likewise, one or more biomarkers, diagnostictests or combinations of biomarkers and diagnostic tests known in theart can be used to determine the progression of the disease or conditionof subjects who have been identified as suffering from aneurodegeneration disorder or a neuropsychiatric disorder. For example,one or more biological markers, neuroimaging markers or combination ofbiological or neuroimaging markers (e.g., MRI, etc.) can be used toidentify subjects at risk of developing AD or, for those subjectsidentified as suffering AD, the progression of the disease. Biologicalmarkers that can be examined include, but are not limited to,beta-amyloid₁₋₄₂, tau, phosphorylated tau (ptau), plasma Aβ antibodies,α-antichymotrypsin, amyloid precursor protein, APP isoform ratio inplatelets, β-secretase (also known as BACE), CD59,8-hydroxy-deoxyguanine, glutamine synthetase, glial fibrillary acidicprotein (GFAP), antibodies to GFAP, interleukin-6-receptor complex,kallikrein, melanotransferrin, neurofilament proteins, nitrotyrosine,oxysterols, sulphatides, synaptic markers, S100β, NPS, plasma signalingproteins, etc., or any combinations thereof (See, Shaw, L., et al.,Nature Reviews 2007, 6, 295-303. Borroni, B., et al., Current Med. Chem.2007, 14, 1171-1178. Phillips, K., et al., Nature Reviews 2006, 5463-469. Bouwman, F. H., et al., Neurology 2007, 69, 1006-1011; Ray, S.,et al., Nature Medicine 2007, 13(11), 1359-1362. Cummings, J., et al.,Neurology 2007, 69, 1622-1634.).

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of the present invention can be varied so as to obtain anamount of the active compound(s) that is effective to achieve thedesired therapeutic response for a particular subject (e.g., a mammal,preferably, a human (patient)), compositions and mode of administration.The selected dosage level will depend upon the activity of theparticular compound, the route of administration, the severity of thecondition being treated and the condition and prior medical history ofthe patient being treated. However, it is within the skill of the art tostart doses of the compound at levels lower than required to achieve thedesired therapeutic effect and to gradually increase the dosage untilthe desired effect is achieved.

Compounds of the present invention can also be administered to a subjectas a pharmaceutical composition comprising the compounds of interest incombination with at least one pharmaceutically acceptable carriers. Thephrase “therapeutically effective amount” of the compound of the presentinvention means a sufficient amount of the compound to treat disorders,at a reasonable benefit/risk ratio applicable to any medical treatment.It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well-known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa subject (namely, a mammal, such as a human) ranges from about 0.01mg/kg body weight to about 100 mg/kg body weight. More preferable dosescan be in the range of from about 0.01 mg/kg body weight to about 30mg/kg body weight. If desired, the effective daily dose can be dividedinto multiple doses for purposes of administration. Consequently, singledose compositions may contain such amounts or submultiples thereof tomake up the daily dose.

e. PHARMACEUTICAL COMPOSITIONS

In yet another embodiment, the present invention provides pharmaceuticalcompositions. The pharmaceutical compositions of the present inventioncomprise the compounds of the present invention or a pharmaceuticallyacceptable salt or solvate thereof. The pharmaceutical compositions ofthe present invention comprise compounds of the present invention thatcan be formulated together with at least one non-toxic pharmaceuticallyacceptable carrier.

In yet another embodiment, the present invention provides apharmaceutical composition comprising compounds of the presentinvention, or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutically acceptable carriers, alone or in combination withone or more compounds that are not the compounds of the presentinvention. Examples of one or more compounds that can be combined withthe compounds of the present invention in pharmaceutical compositions,include, but are not limited to, one or more cognitive enhancing drugs.

The pharmaceutical compositions of this present invention can beadministered to a subject (e.g., a mammal, such as a human) orally,rectally, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments or drops),bucally or as an oral or nasal spray. The term “parenterally” as usedherein, refers to modes of administration which include intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of the present invention for parenteralinjection comprise pharmaceutically acceptable sterile aqueous ornonaqueous solutions, dispersions, suspensions or emulsions as well assterile powders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of the presentinvention include powders, sprays, ointments and inhalants. The activecompound may be mixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives, buffers or propellantswhich may be required. Ophthalmic formulations, eye ointments, powdersand solutions are also contemplated as being within the scope of thisinvention.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq.). Thesalts can be prepared in situ during the final isolation andpurification of the compounds of the invention or separately by reactinga free base function with a suitable organic acid. Representative acidaddition salts include, but are not limited to acetate, adipate,alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate),lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium,triethylammonium, diethylammonium, ethylammonium and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

Esters can be prepared from substrates of formula (I) containing eithera hydroxyl group or a carboxy group by general methods known to personsskilled in the art. The typical reactions of these compounds aresubstitutions replacing one of the heteroatoms by another atom, forexample:

Amides can be prepared from substrates of formula (I) containing eitheran amino group or a carboxy group in similar fashion. Esters can alsoreact with amines or ammonia to form amides.

Another way to make amides from compounds of formula (I) is to heatcarboxylic acids and amines together.

The present invention also contemplates compounds of the presentinvention formed by synthetic means or formed by in vivobiotransformation of a prodrug.

The compounds of the present invention can exist in unsolvated as wellas solvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

f. GENERAL SYNTHESIS

This invention is intended to encompass compounds of the presentinvention whether prepared by synthetic processes or by metabolicprocesses. Preparation of the compounds by metabolic processes includesthose occurring in the human or animal body (in vivo) or processesoccurring in vitro.

The compounds of the present invention may be prepared by a variety ofprocesses well known for the preparation of compounds of this class. Forexample, the compounds of the present invention wherein the groups R¹,R², R³, R⁴, X¹, Y¹, Y², and Y³, have the meanings as set forth in theSummary of the Invention section unless otherwise noted, can besynthesized as shown in Schemes 1-13.

Abbreviations which have been used in the descriptions of the Schemesand the Examples that follow are: Ac for acetyl; aq for aqueous; atm foratmosphere; DCC for dicyclohexylcarbodiimide; DMSO for dimethylsulfoxide; Et for ethyl; EtOAc for ethyl acetate; EtOH for ethanol; ESIfor electrospray ionization; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HPLC for high performance liquid chromatography;LC/MS for liquid chromatography/mass spectroscopy; Me for methyl; MeOHfor methanol; MP for macroporous poly(styrene-co-divinylbenzene) resin;MP-CNBH₃ for cyanoborohydride reagent supported on a macroporous resin;OAc for acetate; psi for pounds per square inch; SFC for supercriticalfluid chromatography; and TFA for trifluoroacetic acid.

Compounds of formula (1-5), wherein R², R³, R⁴, and X¹ are as defined informula (I), can be prepared as described in Scheme 1. N-Arylation of asuitably-protected piperazine-2-carboxylate of formula (1-2), wherein R′is alkyl and P is a suitable nitrogen protecting group, including, butnot limited to tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, orbenzyloxycarbonyl, with a 2-haloarylnitrile of formula (1-1), whereinHal is a halogen, can be accomplished to provide the aminonitrile offormula (1-3). The arylation reaction can be accomplished bynucleophilic aromatic substitution in the presence of a base, oralternatively using transition metal-mediated processes such as thePd-catalyzed process developed by Hartwig and Buchwald (for a review ofthis process, see: J. Am. Chem. Soc. (2006), 128, 3584-3591 andreferences therein). For the base-mediated process, a nitro substituenton the aryl ring as shown with compounds of formula (1-6) can serve tofacilitate the nucleophilic substitution giving compounds of formula(1-7). The nitro group in compounds of formula (1-7) can then be reducedto an amine, and further elaborated by acylation, reductive aminationand other N-functionalization reactions known to one skilled in the art,or replaced by diazotization and captured by halogen, hydroxyl, cyano,or hydride, according to procedures well-known to one skilled in the artto provide compounds of formula (1-3). The cyano moiety of compounds offormula (1-3) can be reduced resulting in formation of cyclizedcompounds of formula (1-4). The nitrogen protecting group, P, can beremoved with standard methods dependent on the particular protectinggroup to give compounds of formula (1-5). Alternatively, P can besubstituent R¹ as defined in the claims, wherein compounds of formula(1-4) are representative of compounds of formula (I).

As shown in Scheme 2, compounds of formula (1-5) can be furtherelaborated to compounds of formulas (2-2), (2-4), (2-6), and (2-8). Forexample, compounds of formula (1-5) can be reacted with an acid chlorideof formula Z¹COCl to give compounds of formula (2-1) Alternatively,compounds of formula (1-5) can be reacted with a carboxylic acid offormula Z¹CO₂H and an amide coupling reagent such as, but not limitedto, dicyclohexylcarbodiimide (DCC) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), to produce compounds of formula (2-1),wherein Z¹ is alkyl, G¹, OR⁶ or NR⁷R⁵ wherein G¹, R⁶, R⁷ and R⁸ are asdefined in the Summary of the Invention. Alternatively, alkylation ofcompounds of formula (1-5) with a compound of formula Z³-LG givescompounds of formula (2-3). Z³ is alkyl, haloalkyl or—(CR^(4a)R^(5a))_(m)G¹ wherein R^(4a), R^(5a), m, and G¹ are as definedin the Summary of the Invention, and LG is a suitable leaving group suchas a halide or a sulfonate. Compounds of formula (1-5) can be reductivealkylated with a ketone or aldehyde of formula Z³C(O)Z⁴, wherein Z⁴ ishydrogen or alkyl, in the presence of a reducing agent such as NaBH₃CNor H₂ in combination with a noble metal catalyst, to form compounds offormula (2-5). Reaction of compounds of formula (1-5) with a sulfonylchloride of formula G¹SO₂Cl will provide sulfonamides of formula (2-7).Further elaboration of the lactam nitrogen of compounds of formulas(2-1), (2-3), (2-5) and (2-7) for example by deprotonation by a basesuch as NaH, followed by addition of an alkylating agent of formulaZ²-LG provides compounds of formulas (2-2), (2-4), (2-6) and (2-8),respectively. Z² is alkyl, —(CR^(4a)R^(5a))_(m)G,—(CR^(4a)R^(5a))_(m)G², wherein R^(4a), R^(5a), m, G¹, and G² are asdefined in the Summary of the Invention. Compounds of formulas (2-1),(2-2), (2-3), (2-4), (2-5), (2-6), (2-7) and (2-8) are representative ofcompounds of formula (I).

As depicted in Scheme 3, compounds of formulas (3-3), (3-5), (3-7),(3-9), (3-11), and (3-13), wherein R¹, R², R³, R⁴, and X¹ are asdescribed in the Summary of the Invention can be prepared from compoundsof formula (3-1). Compounds of formula (3-1) are in turn prepared fromcompounds of formula (1-4) by treatment with a suitable reducing agent,for example BH₃ or AlH₃ complexes. Compounds of formula (3-1) can beacylated with an acyl chloride of formula Z⁵COCl or coupled with acarboxylic acid of formula Z⁵CO₂H to give compounds of formula (3-2). Z⁵is G¹, G², -G²-G¹, —(CR^(4a)R^(5a))_(m)-G¹, —(CR^(4a)R^(5a))_(m)-G², or—CH═CH-G¹, wherein G¹, G², R^(4a), R^(5a), and m are as defined in theSummary of the Invention. Reaction of Z⁵COCl and compounds of formula(3-1) in the presence of a base provides compounds of formula (3-2).Compounds of formula (3-2) are also formed by reacting compounds offormula (3-1) with Z⁵CO₂H in the presence of an amide bond formingreagent such as dicyclohexylcarbodiimide (DCC) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU). Reaction of compounds of formula (3-1) withan alkylating reagent of formula Z⁶-LG supplies compounds of formula(3-4), wherein Z⁶ is —(CR^(4a)R^(5a))_(m)-G¹ or —(CR^(4a)R^(5a))_(m)-G²and LG is a suitable leaving group such as a halide or a sulfonate.Reductive alkylation of compounds of formula (3-1) with an aldehyde orketone of formula Z³C(O)Z⁴ under conditions to reduce the intermediateimine or iminium compound, for example NaBH₃CN or hydrogen and a noblemetal catalyst, will afford compounds of formula (3-6). Z³ is alkyl,haloalkyl or —(CR^(4a)R^(5a))_(m)G¹ wherein R^(4a), R^(5a), m, and G¹are as defined in the Summary of the Invention, and Z⁴ is hydrogen oralkyl. Reaction of compounds of formula (3-1) with a sulfonyl chlorideof formula G¹SO₂Cl will produce compounds of formula (3-8), whilereaction with isocyanates of formula G¹NCO or carbamyl chlorides offormula G¹Z³NCOCl will access compounds of formula (3-10). Additionally,chloroformates of formula Z²O₂CCl react with compounds of formula (3-1)to form the carbamates of formula (3-12). Z² is alkyl,—(CR^(4a)R^(5a))_(m)G¹, —(CR^(4a)R^(5a))_(m)G².

The protective group P in each of the compounds of formulas (3-2),(3-4), (3-6), (3-8), (3-10), or (3-12) can be removed by methodologyknown to one skilled in the art. The revealed piperazine nitrogen of thecompounds of formulas (3-2), (3-4), (3-6), (3-8), (3-10), or (3-12) canthen be subjected to the sequences described in Scheme 2 to givecompounds of formulas (3-3), (3-5), (3-7), (3-9), (3-11), and (3-13),respectively, which are representative of compounds of formula (I).

Compounds of formulas (2-1), (2-2), (2-3), (2-4), (2-5), (2-6), (2-7),and (2-8), wherein G¹, R¹, R², R³, R⁴, and X¹ are as defined in theSummary of the Invention and Z¹, Z², Z³, and Z⁴ are as defined in Scheme2 can be treated with a suitable reducing agent, for example LiAlH₄, BH₃or its complexes, or A1H₃ or an amine complex thereof, to effectreduction of the lactam to provide compounds of formulas (4-1), (4-2),(4-3) and (4-4), respectively. In the case of compounds of formula(4-1), the reducing agent can be used to effect further reduction of theacylamide to form the compound of formula (4-5). Compounds of formulas(4-1), (4-2), (4-3), (4-4), and (4-5) are representative of compounds offormula (I).

Compounds of formula (5-4), wherein R², R³, R⁴ and X¹ are as defined inthe Summary of the Invention, can be prepared as outlined in Scheme 5.Nucleophilic aromatic substitution of a suitable nitroarene of formula(5-1), wherein LG¹ is a halogen or other leaving group, with apiperazin-2-yl acetate derivative of formula (5-2), wherein Z⁴ ishydrogen or alkyl and P is a nitrogen protecting group deliverscompounds of formula (5-3). A two-step sequence of reduction followed bycyclization transforms compounds of formula (5-3) to compounds offormula (5-4). Reduction of the nitro group in compounds of formula(5-3) can be achieved using hydrogenation in the presence of a noblemetal catalyst or, alternatively, iron, tin or SnCl₂ in the presence ofacid as known to one skilled in the art. In the case where Z⁴ is H,cyclization to provide compounds of formula (5-4) can be accomplished byreaction with an amide coupling reagent such as dicyclohexylcarbodiimide(DCC) or O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU). In the case where Z⁴ is alkyl, cyclizationcan be achieved by treatment with acid or with base.

The compounds of formulas (5-4) can be processed to remove the nitrogenprotecting group P, using methods appropriate to that protecting groupand known to those skilled in the art, to provide compounds of formula(6-1), where R², R³, R⁴ and X¹ are as described in the Summary of theInvention. Compounds of formula (6-1) can then be converted to compoundsof formulas (6-2), (6-4), (6-6) and (6-8) using the procedures describedin Scheme 2 for the conversion of compounds of formula (1-5) to thecompounds of formula (2-1), (2-3), (2-5) and (2-7), respectively. Z¹, Z³and Z⁴ are as described in Scheme 2, G¹ is as described in the Summaryof the Invention, and LG is a suitable leaving group such as a halide ora sulfonate. Further elaboration of the lactam nitrogen of compounds offormulas (6-2), (6-4), (6-6) and (6-8) for example by deprotonation by abase such as NaH, followed by addition of an alkylating agent of formulaZ²-LG provides compounds of formulas (6-3), (6-5), (6-7) and (6-9),respectively. Z² is alkyl, —(CR^(4a)R^(5a))_(m)G¹, or—(CR^(4a)R^(5a))_(m)G², wherein R^(4a), R^(5a), m, G¹, and G² are asdefined in the Summary of the Invention. Compounds of formulas (6-2),(6-3), (6-4), (6-5), (6-6), (6-7), (6-8) and (6-9) are representative ofcompounds of formula (I).

As described in Scheme 7, compounds of formulas (6-2)/(6-3),(6-4)/(6-5), (6-6)/(6-7), and (6-8)/(6-9) wherein G¹, R², R³, R⁴, and X¹are as described in the Summary of the Invention, and Z¹, Z², Z³ and Z⁴are as described in Scheme 6 can be reduced to compounds of formulas(7-1), (7-2), (7-3), and (7-4), respectively, with a boron or aluminumhydride, including but not limited to LiAlH₄ or BH₃ complexes, known toeffect reduction of lactams. In the case of compounds of formula (7-1),it is also possible to reduce the amide carbonyl to provide compounds offormula (7-5). Compounds of formulas (7-1), (7-2), (7-3), (7-4), and(7-5) are representative of compounds of formula (I).

As depicted in Scheme 8, compounds of formulas (8-3), (8-5), (8-7),(8-9), (8-11), and (8-13), wherein R¹, R², R³, R⁴, and X¹ are asdescribed in the Summary of the Invention can be prepared from compoundsof formula (8-1). Compounds of formula (8-1) are in turn prepared fromcompounds of formula (5-4) by treatment with a suitable reducing agent,for example BH₃ or A1H₃ complexes. Compounds of formula (8-1) can beacylated with an acyl chloride of formula Z⁵COCl or coupled with acarboxylic acid of formula Z⁵CO₂H to give compounds of formula (8-2). Z⁵is G¹, G², -G²-G¹, —(CR^(4a)R^(5a))_(m)-G¹, —(CR^(4a)R^(5a))_(m)-G², or—CH═CH-G¹, wherein G¹, G², R^(4a), R^(5a), and m are as defined in theSummary of the Invention. Reaction of Z⁵COCl and compounds of formula(8-1) in the presence of a base provides compounds of formula (8-2).Compounds of formula (8-2) are also formed by reacting compounds offormula (8-1) with Z⁵CO₂H in the presence of an amide bond formingreagent such as dicyclohexylcarbodiimide (DCC) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU). Reaction of compounds of formula (8-1) withan alkylating reagent of formula Z⁶-LG, wherein LG is a suitable leavinggroup such as a halide or a sulfonate, supplies compounds of formula(8-4), wherein Z⁶ is —(CR^(4a)R^(5a))_(m)-G¹ or —(CR^(4a)R^(5a))_(m)-G².Reductive alkylation of compounds of formula (8-1) with an aldehyde orketone of formula Z³C(O)Z⁴ under conditions to reduce the intermediateimine or iminium compound, for example NaBH₃CN or hydrogen and a noblemetal catalyst, will afford compounds of formula (8-6). Z³ is alkyl,haloalkyl or (CR^(4a)R^(5a))_(m)G¹ wherein R^(4a), R^(5a), m, and G¹ areas defined in the Summary of the Invention, and Z⁴ is hydrogen or alkyl.Reaction of compounds of formula (8-1) with a sulfonyl chloride offormula G¹SO₂Cl will produce compounds of formula (8-8), while reactionwith isocyanates of formula G¹NCO or carbamyl chlorides of formulaG¹Z³NCOCl will access compounds of formula (8-10). Additionally,chloroformates of formula Z²O₂CCl react with compounds of formula (8-1)to form the carbamates of formula (8-12). Z² is alkyl,—(CR^(4a)R^(5a))_(m)G¹, —(CR^(4a)R^(5a))_(m)G².

The protective group P in each of the compounds of formulas (8-2),(8-4), (8-6), (8-8), (8-10), or (8-12) can be removed by methodologyknown to one skilled in the art. The revealed piperazine nitrogen of thecompounds of formulas (8-2), (8-4), (8-6), (8-8), (8-10), or (8-12) canthen be reacted with the sequences described in Scheme 6 to givecompounds of formulas (8-3), (8-5), (8-7), (8-9), (8-11), and (8-13),respectively, which are representative of compounds of formula (I).

As shown in Scheme 9, compounds of formula (9-1) which can be preparedwith the methodology described in Scheme 7 can be converted to compoundsof formula (9-3), wherein R¹, R², R³, R⁴, and X¹ are as defined in theSummary of the Invention. Compounds of formula (9-1) can be heated inthe presence of a base such as diisopropylethylamine with compounds offormula (9-2), wherein Hal¹ is fluorine or chlorine, to give compoundsof formula (9-3). One of X³ and X⁴ can be N, the other or both X³ and X⁴can be CH. Compounds of formula (9-3) are representative of compounds offormula (I).

As shown in Scheme 10, Compounds of formula (10-1), wherein R², R³, R⁴,X¹, Y¹, Y² and Y³ are as described in the Summary of the Invention, canbe converted to compounds of formulas (10-2) and (10-3). Accordingly,compounds of formula (10-1) can be reacted with compounds of formula(9-2) using the conditions described in Scheme 9 to give compounds offormula (10-2). Compounds of formula (10-2) are representative ofcompounds of formula (I). Alternatively, compounds of formula (10-1) canbe reacted with compounds of formula, Ar-LG², wherein Ar is an aryl orheteroaryl group and LG² is a leaving group suitable for across-coupling reaction or nucleophilic aromatic substitution reaction,to give compounds of formula (10-3). The arylation reaction can beaccomplished by nucelophilic aromatic substitution in the presence of abase, or alternatively using transition metal-mediated processes such asthe Pd-catalyzed process developed by Hartwig and Buchwald (for a reviewof this process, see: J. Am. Chem. Soc. (2006), 128, 3584-3591 andreferences therein). Compounds of formulas (10-3) are representative ofcompounds of formula (I).

As depicted in Scheme 11, compounds of formulas (11-2), (11-3), (11-4),(11-5), (11-6), and (11-7), wherein R¹, R², R³, R⁴, and X¹ are asdescribed in the Summary of the Invention can be prepared from compoundsof formula (11-1). Compounds of formula (11-1) are in turn prepared asdescribed in Scheme 2 for the preparation of compounds of formula (2-3).Compounds of formula (11-1) can be acylated with an acyl chloride offormula Z⁷COCl or coupled with a carboxylic acid of formula Z⁷CO₂H togive compounds of formula (11-2). Z⁷ is G¹, G², —(CR^(4a)R^(5a))_(m)-G¹,—(CR^(4a)R^(5a))_(m)-G², R^(2b), or (CR^(4a)R^(5a))_(m)—W¹, wherein G¹,G², R^(2b), R^(4a), R^(5a), m, and W¹ are as defined in the Summary ofthe Invention. Reaction of Z⁷COCl and compounds of formula (11-1) in thepresence of a base provides compounds of formula (11-2). Compounds offormula (11-2) are also formed by reacting compounds of formula (11-1)with Z⁷CO₂H in the presence of an amide bond forming reagent such asdicyclohexylcarbodiimide (DCC) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU). Reductive alkylation of compounds of formula(11-1) with an aldehyde or ketone of formula Z⁴C(O)Z⁸ under conditionsto reduce the intermediate imine or iminium compound, for exampleNaBH₃CN, macroporous poly(styrene-co-divinylbenzene) cyanoborohydrideresin or hydrogen and a noble metal catalyst, will afford compounds offormula (11-3). Z⁴ is hydrogen or alkyl and Z⁸ is alkyl, G¹ or G²wherein G¹ and G² are as defined in the Summary of the Invention, or Z⁴and Z8 taken together to the atom to which they are attached form a G²group. Reaction of compounds of formula (11-1) with a sulfonyl chlorideof formula G¹SO₂Cl will produce compounds of formula (11-4), whilereaction with isocyanates of formula G¹NCO or carbamyl chlorides offormula G¹Z³NCOCl, wherein Z³ is alkyl, haloalkyl or—(CR^(4a)R^(5a))_(m)G¹ will access compounds of formula (11-5).Compounds of formula (11-1) can also be reacted with triphosgene in thepresence of a base such as but not limited to diisopropylethylamine andZ⁹—NH—Z¹⁰, wherein Z⁹ is hydrogen, alkyl, or cyanoalkyl and Z¹⁰ isalkyl, G¹, G², or —(CR^(4a)R^(5a))_(m)—W², wherein W² is as described inthe Summary of the Invention. Additionally, chloroformates of formulaZ²O₂CCl react with compounds of formula (11-1) to form the carbamates offormula (11-7). Z² is alkyl, —(CR^(4a)R^(5a))_(m)G¹,—(CR^(4a)R^(5a))_(m)G². Compounds of formulas (11-2), (11-3), (11-4),(11-5), (11-6), and (11-7) are representative of compounds of formula(I).

As shown in Scheme 12, compounds of formula (1-4), wherein R², R³, R⁴,and X¹ are as defined in formula (I) and P is a suitable nitrogenprotecting group, including, but not limited to tert-butoxycarbonyl,9-fluorenylmethoxycarbonyl, or benzyloxycarbonyl, can be transformed tocompounds of formula (12-1). The lactam nitrogen of compounds offormulas (1-4) can be deprotonation by a base such as NaH, followed byaddition of an alkylating agent of formula Z²-LG provides compounds offormulas (12-1). Z² is alkyl, —(CR^(4a)R^(5a))_(m)G¹, or—(CR^(4a)R^(5a))_(m)G², wherein R^(4a), R^(5a), m, G¹, and G² are asdefined in the Summary of the Invention. Removal of the protecting groupusing conditions known to one skilled in the art delivers compounds offormulas (12-1) that are representative of compounds of formula (I).

As depicted in Scheme 13, compounds of formula (13-1), wherein R², R³,R4 and X1 are as described in the Summary of the Invention, can bereduced with lithium aluminum hydride to give compounds of formula(13-2). Reductive alkylation of compounds of formula (13-2) with analdehyde or ketone of formula Z⁴C(O)Z⁸ under conditions to reduce theintermediate imine or iminium compound, for example NaBH₃CN, macroporouspoly(styrene-co-divinylbenzene) cyanoborohydride resin or hydrogen and anoble metal catalyst, will afford compounds of formula (13-3). Z⁴ ishydrogen or alkyl and Z⁸ is alkyl, G¹ or G² wherein G¹ and G² are asdefined in the Summary of the Invention, or Z⁴ and Z⁸ taken together tothe atom to which they are attached form a G² group. Compounds offormula (13-2) can also be reacted with an acid chloride of formulaZ¹COCl to give compounds of formula (13-4) Alternatively, compounds offormula (13-2) can be reacted with a carboxylic acid of formula Z¹CO₂Hand an amide coupling reagent such as, but not limited to,dicyclohexylcarbodiimide (DCC) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), to produce compounds of formula (13-4),wherein Z¹ is alkyl, G¹, OR⁶ or NR⁷R⁸ wherein G¹, R⁶, R⁷ and R⁸ are asdefined in the Summary of the Invention. Compounds of formula (13-2) canbe reacted with isocyanates of formula G¹NCO to produce ureas of formula(13-5). Compounds of formulas (13-3), (13-4), and (13-5) arerepresentative of compounds of formula (I).

It will be appreciated that the synthetic schemes and specific examplesas illustrated in the Examples section are illustrative and are not tobe read as limiting the scope of the invention as it is defined in theappended claims. All alternatives, modifications, and equivalents of thesynthetic methods and specific examples are included within the scope ofthe claims.

Optimum reaction conditions and reaction times for each individual stepmay vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Examples section. Reactions may be worked up in the conventionalmanner, e.g., by eliminating the solvent from the residue and furtherpurified according to methodologies generally known in the art such as,but not limited to, crystallization, distillation, extraction,trituration and chromatography. Unless otherwise described, the startingmaterials and reagents are either commercially available or may beprepared by one skilled in the art from commercially available materialsusing methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protective Groups in OrganicSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of the invention may be accomplished by methods analogous tothose described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

g. EXAMPLES

The compounds and processes of the present invention will be betterunderstood by reference to the following Examples, which are intended asan illustration of and not a limitation upon the scope of theapplication.

Example 1 tert-butyl5-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylateExample 1A 1-tert-butyl 3-methyl4-(2-cyano-4-nitrophenyl)piperazine-1,3-dicarboxylate

To a solution of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate (80g, 328 mmol) and N,N-diisopropylethylamine (192 mL, 741 mmol) in 300 mLof dry tetrahydrofuran was added 2-fluoro-5-nitrobenzonitrile (36 g, 219mmol) at room temperature. The reaction mixture was heated to reflux for36 hours. The reaction was concentrated and the resulting residue waspurified by silica gel chromatography (30% ethyl acetate in hexane) togive the title compound: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.41 (s, 9H),3.01-3.15 (m, 1H), 3.29-3.36 (m, 1H), 3.34-3.36 (m, 1H), 3.48-3.55 (m,1H), 3.66 (s, 3H), 3.72-3.76 (m, 1H), 4.43-7.48 (m, 1H), 4.96-4.98 (m,1H), 7.30 (d, J=9.1 Hz, 1H), 8.32 (dd, J=9.5, 2.8 Hz, 1H), 8.55 (d,J=2.8 Hz, 1H); MS (DCI/NH₃) m/z 391 (M+H)⁺.

Example 1B 1-tert-butyl 3-methyl4-(2-cyanophenyl)piperazine-1,3-dicarboxylate

To a solution of the product of Example 1A (66 g, 169.2 mmol) in 250 mLof methanol, was added iron dust (66 g, 1178.6 mmol) and a solution ofNH₄Cl (81.5 g, 1523 mmol) in 250 mL of water. The solution was heated toreflux for 1 hour. The reaction was cooled and then methanol was removedin vacuo. The resulting aqueous residue was extracted with ethyl acetate(500 mL). The organic layer was washed twice with brine, dried oversodium sulfate and condensed to give crude 1-tert-butyl 3-methyl4-(4-amino-2-cyanophenyl)piperazine-1,3-dicarboxylate (50 g), which wasdissolved in 35% hypophosphorous acid (250 mL). Copper(I) oxide (1.5 g,10.5 mmol) was added, and the reaction was chilled to 0° C. Sodiumnitrite (11.6 g, 168 mmol) in water (300 mL) was added dropwise at 0° C.with stirring. After 2 hours, the reaction mixture was basified with theaddition of 40% NaOH solution to pH 8 and extracted with ethyl acetate(2×500 mL). The organic layers were combined and washed with water (200mL) and brine (100 mL). The solvent was evaporated to give the crudeproduct which was purified by column chromatography on silica gel (ethylacetate/petroleum ether, 1:10) to give the title compound: MS (DCI/NH₃)m/z 346 (M+H)⁺.

Example 1C tert-butyl5-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate

A mixture of Raney®-nickel (25 g) and the product of Example 1B (35 g,101 mmol) in 1 L of methanol saturated with NH₃ was stirred under a H₂(40 psi) atmosphere at room temperature for 48 hours. The reaction wasfiltered, and the filtrate was condensed under reduced pressure to givethe title compound: ¹H NMR: (300 MHz, CDCl₃) δ ppm 1.49 (s, 9H),2.99-3.25 (m, 4H), 3.47 (dd, J=10.7, 2.8 Hz, 1H), 3.78 (dd, J=13.9, 2.8Hz, 1H), 4.18-4.20 (m, 1H), 4.36-4.40 (m, 1H), 4.87 (dd, J=13.9, 4.8 Hz,1H), 6.14-6.18 (m, 1H) 7.02-7.08 (m, 2H), 7.17 (dd, J=7.1, 1.2 Hz, 1H),7.30-7.36 (m, 1H); MS (DCI/NH₃) m/z 318 (M+H)⁺.

Example 23-benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepineExample 2A2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one

To a solution of the product of Example 1C (32 g, 100.9 mmol) indichloromethane (200 mL) was added trifluoroacetic acid (200 mL) at roomtemperature. After stirring overnight (16 hours), the reaction mixturewas condensed under reduced pressure and diluted with saturated NaHCO₃(100 mL). The aqueous phase was extracted with ethyl acetate (5×100 mL).The organic layer was washed with brine (100 mL), dried over magnesiumsulfate and filtered. The filtrate was concentrated under reducedpressure to give the title compound: ¹H NMR (300 MHz, C₆D6) δ ppm2.57-2.65 (m, 4H), 3.04-3.10 (m, 1H), 3.22 (dd, J=14.3, 7.0 Hz, 1H),3.38-3.44 (m, 2H), 4.28 (dd, J=14.0, 4.9 Hz, 1H), 6.69-3.74 (m, 2H),6.80 (td, J=7.4, 1.1 Hz, 1H), 7.08 (td, J=7.7, 171 Hz, 1H); MS (DCI/NH₃)m/z 218 (M+H)⁺.

Example 2B3-benzyl-2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one

Benzyl bromide (14.9 g, 87.1 mmol) was added dropwise to a mixture ofthe product of Example 2A (18.5 g, 82.9 mmol) and potassium carbonate(45.8 g, 331.8 mmol) in acetonitrile (200 mL) at room temperature withstirring. The reaction mixture was stirred for 3 hours under reflux.Then it was cooled, filtered, and concentrated under reduced pressure togive the crude product which was purified by column chromatography onsilica gel (ethyl acetate) to give the title compound: MS (DCI/NH₃) m/z308 (M+H)⁺.

Example 2C3-benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

To a suspension of LiAlH₄ (8.9 g, 234.6 mmol) in dry tetrahydrofuran(200 mL) was added dropwise a solution of the product of Example 2B (24g, 78.2 mmol) in dry tetrahydrofuran (200 mL) at −78° C. with stirringunder a nitrogen atmosphere. Then it was allowed to warm to roomtemperature slowly and stirred for 60 hours. The reaction mixture wascooled to −78° C., quenched with water (20 mL), diluted with ethylacetate (400 mL), dried over magnesium sulfate and filtered. Thefiltrate was washed with brine twice (2×100 mL), dried over magnesiumsulfate and concentrated under reduced pressure to give the titlecompound: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.24-2.32 (m, 1H), 2.34-2.41(m, 1H), 2.55-2.58 (m, 1H), 2.67-2.75 (m, 3H), 2.84-2.90 (m, 1H),3.08-3.20 (m, 2H), 3.48-3.57 (m, 2H), 3.74 (d, J=12.6 Hz, 1H), 4.02 (d,J=12.6 Hz, 1H), 6.85-6.89 (m, 2H), 7.07 (dd, J=7.6, 1.5 Hz, 1H), 7.18(td, J=7.6, 1.7 Hz, 1H), 7.24-7.30 (m, 1H), 7.31-7.34 (m, 4H); MS(DCI/NH₃) m/z 294 (M+H)⁺.

Example 33-benzyl-6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (344.8 mg, 1.18 mmol), was dissolved inmethanol (10 mL). 4-Bromobenzaldehyde (338.8 mg, 1.56 mmol) was added tothe reaction, and the mixture was stirred for 1 hour at ambienttemperature. Sodium cyanoborohydride (238.9 mg, 3.80 mmol) was thenadded, and the reaction was stirred at ambient temperature for 20 hours.The reaction was then diluted with 1 MNaOH (50 mL) and extracted withdichloromethane (3×50 mL). The organic layers were combined,concentrated and purified by silica gel chromatography (ethylacetate/dichloromethane 1:1, R_(f) 0.37) to give the title compound: ¹HNMR (500 MHz, pyridine-d₅) δ ppm 2.30-2.40 (m, 2H), 2.55 (dd, J=13.4,3.1 Hz, 1H) 2.66-2.71 (m, 2H), 2.77-2.79 (m, 1H), 3.23-3.34 (m, 3H),3.49-3.58 (m, 4H), 3.77 (d, J=13.1 Hz, 1H), 4.05 (d, J=13.1 Hz, 1H),6.97 (dd, J=7.9, 0.9 Hz, 1H), 7.01 (td, J=7.3, 1.2 Hz, 1H), 7.13 (dd,J=7.3, 1.5 Hz, 1H), 7.30-7.36 (m, 4H), 7.39-7.43 (m, 2H), 7.48-7.50 (m,2H), 7.53-7.57 (m, 2H); MS (DCI/NH₃) m/z 462 (M+H)⁺. Elemental analysisis calculated for C₂₆H₂₈BrN₃: C, 67.53; H, 6.10; N, 9.09. Found: C,67.44; H, 5.83; N, 9.08.

The title compound (270.0 mg, 0.58 mmol) was dissolve in warm methanol.Hydrochloric acid in dioxane (4 M, 0.6 mL, 2.4 mmol) was added toprecipitate out the title compound as the bis-hydrochloride salt:Elemental analysis is calculated for C₂₆H₂₈N₃.2 HCl.2 MeOH: C, 57.16; H,6.04; N, 7.41. Found: C, 57.29; H, 6.22; N, 7.39.

Example 41-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-phenylethanone

The product of Example 2 (154.2 mg, 0.53 mmol) was dissolved indichloromethane (5 mL). Diisopropylethylamine (0.20 mL, 1.15 mmol) andphenylacetyl chloride (123.8 mg, 0.80 mmol) were added, and the reactionmixture was stirred for 20 hours at ambient temperature. The reactionwas concentrated and purified by preparative HPLC using the generalammonium acetate method described herein on a Phenomenex® Luna® C8(2) 5μm 100 Å AXIA column (30×75 mm). A gradient of acetonitrile (A) and 10mM ammonium acetate in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-6.0 minutes linear gradient 10-100%A, 6.0-7.0 minutes 100% A, 7.0-8.0 minutes linear gradient 100-10% A).Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). AnAgilent 1100 Series Purification system was used, consisting of thefollowing modules: Agilent 1100 Series LC/MSD SL mass spectrometer withAPI-electrospray source; two Agilent 1100 Series preparative pumps;Agilent 1100 Series isocratic pump; Agilent 1100 Series diode arraydetector with preparative (0.3 mm) flow cell; Agilent active-splitter,IFC-PAL fraction collector/autosampler. The make-up pump for the massspectrometer used 3:1 methanol:water with 0.1% formic acid at a flowrate of 1 mL/minute. Fraction collection was automatically triggeredwhen the extracted ion chromatogram (EIC) for the target mass exceededthe threshold specified in the method. The system was controlled usingAgilent Chemstation (Rev B.10.03), Agilent A2Prep, and Leap FractPalsoftware, with custom Chemstation macros for data export. The desiredfractions were concentrated to give the title compound: ¹H NMR (500 MHz,pyridine-d₅) δ ppm 2.14-4.00 (m, 13H), 4.58 (d, J=12.5 Hz, 1H), 4.83 (d,J=12.2 Hz, 1H), 6.95-6.99 (m, 1H), 7.03-7.07 (m, 1H), 7.24-7.49 (m,11H), 7.53-7.55 (m, 1H); MS (DCI/NH₃) m/z 412 (M+H)⁺; Elemental analysisis calculated for C₂₇H₂₉N₃O.0.2; H₂O: C, 78.12; H, 7.14; N, 10.12.Found: C, 78.23; H, 7.20; N, 10.02.

Example 5(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(phenyl)methanone

The product of Example 2 (130.2 mg, 0.45 mmol) and benzoyl chloride(146.6 mg, 1.04 mmol) were processed according to the procedure forExample 4 to give the title compound: ¹H NMR (500 MHz, benzene-d₆) δ ppm(7:3 mixture of rotomers at 25° C.) 1.74-1.87 (m, 2H), 2.07-2.65 (m,6H), 2.82-2.88 (m, 1.4H), 2.97-3.00 (m, 1H), 3.22 (d, J=12.8 Hz, 0.3H),3.77 (d, J=13.2 Hz, 0.3H), 4.27 (d, J=13.1 Hz, 0.3H), 4.34 (d, J=13.7Hz, 0.3H), 4.59 (d, J=14.0 Hz, 0.7H), 4.78 (d, J=13.7 Hz, 0.7H),6.24-7.18 (m, 14H); MS (DCI/NH₃) m/z 398 (M+H)⁺. Elemental analysis iscalculated for C₂₆H₂₇N₃O.0.2; H₂O: C, 77.85; H, 6.89; N, 10.48. Found:C, 77.87; H, 6.87; N, 10.53.

Example 63,6,6-tribenzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepin-6-ium

The product of Example 2 (102.2 mg, 0.35 mmol) was dissolved in acetone(5 mL). Potassium carbonate (77.3 mg, 0.56 mmol) and benzyl bromide(129.4 mg, 0.76 mmol) were added, and the reaction mixture was stirredfor 2 hours at ambient temperature. The reaction was filtered,concentrated and purified by preparative HPLC (general ammonium acetatemethod described in Example 4, retention time 2.43 minutes) to give thetitle compound as the acetate salt: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.67(t, J=10.0 Hz, 1H), 2.29 (td, J=10.8, 2.8 Hz, 1H), 2.46 (d, J=10.7 Hz,1H), 2.69 (d, J=11.0 Hz, 1H), 2.93 (t, J=9.2 Hz, 1H), 3.50-3.57 (m, 2H),2.99-3.05 (m, 1H), 3.23-3.55 (m, 5H), 7.75-7.78 (m, 2H), 4.99-5.06 (m,2H), 5.20-5.28 (m, 2H), 6.94-6.97 (m, 2H), 7.23-7.24 (m, 2H), 7.29-7.38(m, 6H), 7.42-7.52 (m, 7H), 7.61-7.62 (m, 2H); MS (DCI/NH₃) m/z 474(M+H)⁺.

Example 73,6-dibenzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

Continued elution of Example 6 gave the title compound (retention time2.97 minutes): ¹H NMR (400 MHz, pyridine-d₅) δ ppm 2.31 (td, J=10.2, 4.0Hz, 1H), 2.38 (t, J=10.1 Hz, 1H), 2.56-2.60 (m, 1H), 2.68-2.79 (m, 3H),3.24-3.36 (m, 3H), 3.50-5.38 (m, 2H), 3.59-3.66 (m, 2H), 3.82 (d, J=13.1Hz, 1H), 4.08 (d, J=12.8 Hz, 1H), 6.95-7.02 (m, 2H), 7.12 (dd, J=7.3,1.5 Hz, 1H), 7.29-7.35 (m, 3H), 7.38-7.42 (m, 4H), 7.48-7.51 (m, 4H); MS(DCI/NH₃) m/z 384 (M+H)⁺.

Example 83-benzyl-6-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (151.1 mg, 0.52 mmol) was dissolved in formicacid (4 mL). A solution of formaldehyde (36 weigh t %, 1 mL) was added,and the reaction mixture was heated to 100° C. for 1 hour. The reactionwas concentrated and purified by preparative HPLC (general ammoniumacetate method described in Example 4) to give the title compound as theacetic acid salt: ¹H NMR (500 MHz, CDCl₃) δ ppm 2.03 (s, 3H, CH₃CO₂H),2.29-2.35 (m, 2H), 2.45 (s, 3H), 2.61 (dd, J=13.6, 3.2 Hz, 1H),2.74-2.80 (m, 2H), 2.86-2.88 (m, 1H), 3.27-3.37 (m, 3H), 3.55-5.63 (m,2H), 3.80 (d, J=13.1 Hz, 1H), 4.19 (d, J=12.8 Hz, 1H), 6.89-6.95 (m,2H), 7.13-7.15 (m, 1H), 7.28-7.37 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δppm 22.26 (CH₃CO₂H), 43.45, 49.83, 53.15, 54.15, 56.15, 57.43, 57.46,63.00, 118.59, 121.41, 125.18, 127.24, 128.29, 129.31, 129.63, 130.53,137.53, 148.82, 176.00 (CH₃CO₂H); MS (DCI/NH₃) m/z 308 (M+H)⁺.

Example 93-benzyl-6-(pyrimidin-2-yl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (108.3 mg, 0.37 mmol) was dissolved in dimethylsulfoxide (1 mL). Diisopropylethylamine (0.12 mL, 0.69 mmol) and2-chloropyrimidine (77.7 mg, 0.68 mmol) were added, and the reactionmixture was heated to 100° C. for 16 hours. The reaction was dilutedwith methanol (1 mL) and purified by preparative HPLC using the generaltrifluoroacetic acid method on a Phenomenex Luna C8(2) 5 μm 100 Å AXIAcolumn (30×75 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A).Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). Acustom purification system was used, consisting of the followingmodules: Waters LC4000 preparative pump; Waters 996 diode-arraydetector; Waters 717+ autosampler; Waters SAT/IN module, Alltech VarexIII evaporative light-scattering detector; Gilson 506C interface box;and two Gilson FC204 fraction collectors. The system was controlledusing Waters Millennium32 software, automated using an Abbott developedVisual Basic application for fraction collector control and fractiontracking. Fractions were collected based upon UV signal threshold andselected fractions subsequently analyzed by flow injection analysis massspectrometry using positive APCI ionization on a Finnigan LCQ using70:30 methanol: 10 mM NH₄OH(aq) at a flow rate of 0.8 mL/minute.Loop-injection mass spectra were acquired using a Finnigan LCQ runningLCQ Navigator 1.2 software and a Gilson 215 liquid handler for fractioninjection controlled by an Abbott developed Visual Basic application.The title compound was obtained as the bis-trifluoroacetate: ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.45-2.53 (m, 2H), 3.04-3.22 (m, 5H), 3.36 (td,J=11.4, 2.6 Hz, 1H), 3.67 (d, J=12.8 Hz, 1H), 3.75 (d, J=13.1 Hz, 1H),4.66 (dd, J=15.0, 1.5 Hz, 1H), 4.78 (d, J=13.7 Hz, 1H), 4.85 (d, J=13.7Hz, 1H), 6.50 (t, J=4.7 Hz, 1H), 6.99 (d, J=7.9 Hz, 1H), 7.09 (t, J=7.3Hz, 1H), 7.30-7.39 (m, 5H), 7.48 (d, J=7.0 Hz, 1H); MS (DCI/NH₃) m/z 372(M+H)⁺. Elemental analysis is calculated for C₂₃H₂₅N₅.2.4 TFA.H₂O: C,50.35; H, 4.47; N, 10.56; F, 20.63. Found: C, 50.57; H, 4.34; N, 10.34;F, 20.60.

Example 10(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(4-fluorophenyl)methanone

The product of Example 2 (103.8 mg, 0.35 mmol) and 4-fluorobenzoylchloride (106.6 mg, 0.67 mmol) were processed according to the procedurefor Example 4 and purified by silica gel chromatography (25%->50% ethylacetate in dichloromethane, R_(f) 0.33->0.45) to give the titlecompound: ¹H NMR (500 MHz, pyridine-d₅) δ ppm (mixture of rotomers at25° C.) 2.24-3.63 (m, 11H), 4.42 (d, J=12.8 Hz, 0.3H), 4.72 (d, J=12.8Hz, 0.3H), 4.88 (d, J=14.0 Hz, 0.7H), 5.10 (d, J=14.0 Hz, 0.7H),6.95-7.67 (m, 13H); MS (DCI/NH₃) m/z 416 (M+H)⁺. Elemental analysis iscalculated for C₂₆H₂₆FN₃O.0.1; H₂O: C, 74.83; H, 6.33; N, 10.07. Found:C, 74.62; H, 6.04; N, 10.03.

Example 113-benzyl-6-(pyrazin-2-yl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (103.8 mg, 0.35 mmol) and 2-chloropyrazine(106.7 mg, 0.93 mmol) were processed according to the procedure forExample 9. The reaction was purified by preparative HPLC as described inExample 9 to give the title compound as the tris-trifluoroacetic acidsalt: ¹H NMR (400 MHz, pyridine-d₅) δ ppm 2.45-2.55 (m, 2H), 3.09-3.21(m, 5H), 3.40 (td, J=11.5, 2.9 Hz, 1H), 3.71-3.80 (m, 2H), 4.43-4.47 (m,2H), 4.68 (d, J=12.5 Hz, 1H), 7.00 (dd, J=7.9, 0.9 Hz, 1H), 7.12 (td,J=7.4, 1.1 Hz, 1H), 7.30-7.42 (m, 5H), 7.47-7.48 (m, 2H), 8.03 (d, J=2.8Hz, 1H), 8.15 (dd, J=2.8, 1.5 Hz, 1H), 8.35 (d, J=1.5 Hz, 1H); MS(DCI/NH₃) m/z 372 (M+H)⁺. Elemental analysis calculated for C₂₃H₂₅N₅.3TFA: C, 48.84; H, 3.96; N, 9.81. Found: C, 49.21; H, 4.06; N, 9.94.

Example 12(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(pyrazin-2-yl)methanone

The product of Example 2 (101.5 mg, 0.35 mmol) and 2-pyrazinecarbonylchloride (74.8 mg, 0.53 mmol) were processed according to the procedurefor Example 4 to give the title compound: ¹H NMR (400 MHz, pyridine-d₅)δ ppm 2.45-2.55 (m, 2H), 3.09-3.21 (m, 5H), 3.40 (td, J=11.5, 2.9 Hz,1H), 3.71-3.80 (m, 2H), 4.43-4.47 (m, 2H), 4.68 (d, J=12.5 Hz, 1H), 7.00(dd, J=7.9, 0.9 Hz, 1H), 7.12 (td, J=7.4, 1.1 Hz, 1H), 7.30-7.42 (m,5H), 7.47-7.48 (m, 2H), 8.03 (d, J=2.8 Hz, 1H), 8.15 (dd, J=2.8, 1.5 Hz,1H), 8.35 (d, J=1.5 Hz, 1H); MS (DCI/NH₃) m/z 400 (M+H)⁺. Elementalanalysis calculated for C₂₄H₂₅N₅O.0.15H₂O: C, 71.67; H, 6.34; N, 17.41.Found: C, 71.61; H, 6.24; N, 17.40.

Example 13(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1-phenylcyclopropyl)methanone

The product of Example 2 (101.8 mg, 0.35 mmol) and1-phenyl-cyclopropanecarbonyl chloride (98.9 mg, 0.55 mmol) wereprocessed according to the procedure for Example 4 to give the titlecompound: ¹H NMR (400 MHz, pyridine-d₅) δ ppm (1:1 mixture of rotomersat 25° C.) 1.10-1.71 (m, 4H), 2.05-2.28 (m, 2H), 2.41-2.47 (m, 0.5H),2.71-2.80 (m, 1.5H), 2.95-3.15 (m, 4H), 3.41-3.51 (m, 1.5H), 3.62-3.65(m, 0.5H), 3.81-3.85 (m, 0.5H), 4.52-4.62 (m, 1.5H), 4.83 (d, J=13.4 Hz,0.5H), 5.13 (d, J=13.7 Hz, 0.5H), 6.90-7.03 (m, 2.5H), 7.15-7.48 (m,11.5H); (MS (DCI/NH₃) m/z 438 (M+H)⁺. Elemental analysis calculated forC₂₉H₃₁N₃O.0.2H₂O: C, 78.95; H, 7.17; N, 9.52. Found: C, 78.96; H, 7.12;N, 9.56.

Example 14(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(morpholin-4-yl)methanone

The product of Example 2 (1.00 g, 3.41 mmol) was dissolved indichloromethane (15 mL). N,N-Diisopropylethylamine (0.90 mL, 5.15 mmol)and 4-morpholinecarbonyl chloride (0.61 g, 4.09 mmol) were added, andthe reaction mixture was stirred at ambient temperature for 16 hours.The reaction was concentrated and purify by silica gel chromatography(ethyl acetate, R_(f) 0.27) to give the title compound: ¹H NMR (300 MHz,CDCl₃) δ ppm 2.27-2.41 (m, 2H), 2.68-2.91 (m, 2H), 3.07-3.34 (m, 8H),3.57-3.77 (m, 4H), 4.24 (d, J=12.6 Hz, 1H), 4.67 (d, J=12.6 Hz, 1H),6.90-6.99 (m, 2H), 7.13-7.16 (m, 1H), 7.27-7.33 (m, 6H); MS (DCI/NH₃)m/z 407 (M+H)⁺. Elemental analysis calculated for C₂₄H₃₀N₄O₂.0.25H₂O: C,70.13; H, 7.48; N, 13.63. Found: C, 70.02; H, 7.34; N, 13.67.

Example 15(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)[trans-2-phenylcyclopropyl]methanone

The product of Example 2 (112.0 mg, 0.38 mmol) andtrans-2-phenyl-1-cyclopropanecarbonyl chloride (101.4 mg, 0.51 mmol)were processed according to the procedure for Example 4 to give thetitle compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.24-3.72 (m, 12H),4.31-4.91 (m, 5H), 6.91-7.35 (m, 14H); (MS (DCI/NH₃) m/z 438 (M+H)⁺.

Example 163-benzyl-6-(pyridin-2-yl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (100.0 mg, 0.34 mmol) and 2-fluoropyridine(73.8 mg, 0.76 mmol) were processed according to the procedure forExample 9. The reaction was purified by preparative HPLC using themethod described in Example 4 to give the title compound: ¹H NMR (400MHz, pyridine-d₅) δ ppm 2.14-2.28 (m, 2H), 2.74-2.77 (m, 1H), 2.29-3.07(m, 3H), 3.17-3.31 (m, 3H), 3.42-3.45 (m, 1H), 4.44 (d, J=12.2 Hz, 1H),4.65 (dd, J=15.1, 2.0 Hz, 1H), 4.73 (d, J=12.5 Hz, 1H), 6.62 (dd, J=7.0,4.9 Hz, 1H), 6.66 (d, J=8.5 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 7.09 (td,J=7.4, 1.1 Hz, 1H), 7.28-7.42 (m, 7H), 7.50-7.54 (m, 1H), 8.34-8.35 (m,2H); MS (DCI/NH₃) m/z 371 (M+H)⁺. Elemental analysis calculated forC₂₄H₂₆N₄.0.3H₂O: C, 76.69; H, 7.13; N, 14.90. Found: C, 76.40; H, 6.76;N, 14.54.

Example 173-benzyl-6-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (127.2 mg, 0.43 mmol) was dissolved in methanol(5 mL). 4-Fluorobenzaldehyde (85.0 mg, 0.69 mmol) was added, and thereaction mixture was stirred at ambient temperature for 1 hour. Sodiumcyanoborohydride (58.1 mg, 0.93 mmol) was then added, and the reactionwas stirred at ambient temperature for 20 hours. The reaction was thendiluted with 1 MNaOH (25 mL) and extracted with dichloromethane (3×25mL). The organic layers were combined, concentrated and purified bypreparative HPLC using the method described in Example 9 to give thetitle compound as the tris-trifluoroacetic acid salt: ¹H NMR (300 MHz,CDCl₃) δ ppm 2.73-2.79 (m, 1H), 3.05-3.13 (m, 2H), 3.38-3.42 (m, 2H),3.65-3.95 (m, 5H), 4.02 (d, J=12.7 Hz, 1H), 4.15 (d, J=5.6 Hz, 1H), 4.19(d, J=5.9 Hz, 1H), 4.33 (d, J=12.7 Hz, 1H), 4.91 (d, J=13.5 Hz, 1H),7.93 (d, J=7.9 Hz, 1H), 7.11-7.19 (m, 2H), 7.19-7.29 (m, 2H), 7.43-7.56(m, 8H); MS (DCI/NH₃) m/z 402 (M+H)⁺. Elemental analysis is calculatedfor C₂₆H₂₈FN₃.2.65 TFA: C, 53.42; H, 4.39; N, 5.97. Found: C, 53.32; H,4.60; N, 5.99.

Example 18(−)-3-benzyl-6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The free based product of Example 3 (200.3 mg, 0.43 mmol) was separatedin to individual enantiomers by SFC purification carried out using amodified Berger Instruments PrcpSFC™ system. A manual version of theBerger system was integrated with a Gilson 232 autosampler for sampleinjection and a Cavro MiniPrep™ pipettor customized for fractioncollection at atmospheric pressure (Olson, J.; et al. JALA 2002, 7,69-74). Custom designed collection shoes allowed collection into 18×150mm tubes and a methanol wash system allows washing of shoes betweenfractions to maximize recovery and avoid cross-contamination offractions. The system was controlled using SFC ProNTo™ software (version1.5.305.15) and an Abbott developed Visual Basic application forautosampler and fraction collector control. The outlet pressure was 100bar, oven temperature at 35° C., and mobile phase flow rate at 40mL/minute (DaiceUChiral Technologies Chiralpak® AD-H column, 5-50%methanol:CO₂ 100 bar+0.1% diethylamine). The preparative SFC system wascontrolled using SFC ProNTo™ software (version 1.5.305.15) and customsoftware for autosampler and fraction collector control. Fractions werecollected based upon UV signal threshold and on-line Thermo MSQ massspectrometry was used for molecular mass confirmation, using ESIionization in positive mode. Mass spectra were acquired using aNavigator4.0 software and an Abbott developed Visual Basic interface tocommunicate with SFC controlling software. The SFC retention time was15.60 minutes. [α]²⁰ _(D)=−12° (c 0.91, CH₂Cl₂).

Example 19(+)-3-benzyl-6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The enantiomer of the above compound was obtained in the same separationprocedure as described in Example 18. The SFC retention time was 16.39minutes. [α]²⁰ _(D)=+13° (c 0.94, CH₂Cl₂).

Example 20(2E)-1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-3-phenylprop-2-en-1-one

The product of Example 2 (98.9 mg, 0.34 mmol) and trans-cinnamoylchloride (103.9 mg, 0.62 mmol) were processed according to the procedurefor Example 4 to give the title compound: ¹H NMR (500 MHz, benzene-d₆) δppm (1:1 mixture of rotomers at 25° C.) 2.03-2.15 (m, 1.5H), 2.41-2.51(m, 1.5H), 2.57-2.65 (m, 1H), 2.71-2.82 (m, 2H), 2.93-2.98 (m, 3H), 4.19(d, J=11.9 Hz, 0.5H), 4.61 (d, J=13.1 Hz, 0.5H), 4.74-4.79 (m, 1H), 5.10(d, J=14.3 Hz, 0.5H), 6.57 (d, J=15.6 Hz, 0.5H), 6.70-6.74 (m, 1H),6.85-6.91 (m, 2H), 6.98-6.99 (m, 0.5H), 7.05-7.35 (m, 9H), 8.12-8.17 (m,1H); MS (DCT/NH₃) m/z 424 (M+H)⁺. Elemental analysis is calculated forC₂₈H₂₉N₃O.0.3H₂O: C, 78.40; H, 6.96; N, 9.80. Found: C, 78.36; H, 6.79;N, 9.65.

Example 213-benzyl-6-[4-(trifluoromethyl)benzyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (99.8 mg, 0.34 mmol) and4-(trifluoromethyl)benzaldehyde (96.7 mg, 0.55 mmol) were processedaccording to the procedure for Example 17 and purified by preparativeHPLC using the method described in Example 9 to give the title compoundas the tris-trifluoroacetic acid salt: ¹H NMR (300 MHz, pyridine-d₅) δppm 2.54 (dt, J=10.8, 3.4 Hz, 1H) 2.62-2.74 (m, 3H), 2.95 (d, J=10.7 Hz,1H), 3.01 (d, J=11.0 Hz, 1H), 3.32-3.43 (m, 2H), 3.50-3.52 (m, 1H),3.69-3.84 (m, 5H), 4.16 (d, J=13.1 Hz, 1H), 6.95 (d, J=7.9, 1H), 7.04(t, J=7.0 Hz, 1H), 7.17 (dd, J=7.3, 1.2 Hz, 1H), 7.32-7.37 (m, 2H),7.39-7.42 (m, 2H), 7.54-7.53 (m, 2H), 7.60-7.61 (m, 2H), 7.67-7.68 (m,2H); MS (DCI/NH₃) m/z 452 (M+H)⁺. Elemental analysis is calculated forC₂₇H₂₈F3N₃.3 TFA: C, 49.94; H, 3.94; N, 5.29; F, 28.73. Found: C, 50.11;H, 3.83; N, 5.36; F, 28.52.

Example 227-(4-bromobenzyl)-3-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepineExample 22A methyl (1,4-dibenzylpiperazin-2-yl)acetate

Methyl 4-bromocrotonate (Aldrich, 5.53 mL, 40 mmol) was added dropwisewith stirring to an ice-cooled solution of triethylamine (11.15 mL, 80mmol) and N,N′-dibenzylethylenediamine (Aldrich, 9.67 mL, 40 mmol) intoluene (200 mL). The solution was stirred with ice cooling for 1 hour,then allowed to warm gradually to room temperature and stirred 25 hourslonger. The mixture was filtered through a pad of diatomaceous earthwith an ethyl acetate (20 mL) rinse. The filtrate was concentrated to anoil, which was mixed with 10% aqueous HCl (240 mL). After 5 minutes, themixture was filtered and the cake was rinsed with water (2×10 mL). Thefiltrate was washed with ethyl acetate (2×80 mL) and the aqueous phasewas made basic (pH˜9-10) by portionwise addition of solid K₂CO₃ (26 g),then 25% aqueous NaOH (10 mL). The turbid mixture was extracted withethyl acetate (3×120 mL) and the combined extracts were washed withbrine (100 mL), dried (MgSO₄) and concentrated under vacuum to leave thetitle compound as an oil (9.78 g): ¹H NMR (300 MHz, CDCl₃) δ ppm2.30-2.47 (m, 4H), 2.49-2.73 (m, 4H), 3.06-3.18 (m, 1H), 3.43 (d, J=13.2Hz, 2H), 3.53 (d, J=13.2 Hz, 1H), 3.60 (s, 3H), 3.76 (d, J=13.6 Hz, 1H),7.14-7.36 (m, 10H); MS (DCI) m/z 339 (M+H)⁺.

Example 22B t-butyl 3-(methoxycarbonylmethyl)piperazine-1-carboxylate

The product of example 22A (9.78 g, 28.9 mmol) was combined with 20%Pd(OH)₂—C (wet, 1.96 g) in methanol (100 mL) and 12 Maqueous HCl (2.9mL, 35 mmol). The mixture was stirred under hydrogen (30 psi) at roomtemperature for 22 hours, then filtered and concentrated under vacuum.The residue was combined with 20% aqueous K₂CO₃ (40 mL) and ethylacetate (50 mL), and the mixture stirred with ice-cooling as2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (Aldrich, 7.12 g,28.9 mmol) was added gradually over 5 minutes. The mixture was stirredwith ice cooling for 1 hour, then it was allowed to warm to roomtemperature for 2 hours. The mixture was extracted with ethyl acetate(2×100 mL) and the combined ethyl acetate washes were extracted with 10%aqueous HCl (40 mL). The aqueous layer was washed with ethyl acetate (30mL), then made basic (pH ˜9) by gradual addition of solid K₂CO₃ (11.8g). Ethyl acetate (80 mL) was added, and the mixture was stirred at roomtemperature for 30 minutes. The aqueous phase was separated, and theorganic phase was washed with brine (50 mL), dried (MgSO₄) andconcentrated under vacuum to leave the title compound: ¹H NMR (300 MHz,CDCl₃) δ ppm 1.46 (s, 9H), 2.31-2.49 (m, 2H), 2.50-2.68 (m, 1H),2.72-2.81 (m, 1H), 2.82-2.98 (m, 2H), 2.98-3.09 (m, 1H), 3.70 (s, 3H),3.90 (d, J=9.9 Hz, 2H); MS (DCI) m/z 259 (M+H)⁺.

Example 22C2-(4-(t-butoxycarbonyl)-1-(2-nitrophenyl)piperazin-2-yl)acetic acid

Solid K₂CO₃ (1070 mg, 7.74 mmol) was added to a mixture of1-fluoro-2-nitrobenzene (655 mg, 4.65 mmol) and the product of Example22B (1000 mg, 3.87 mmol). Dimethyl sulfoxide (40 mL) was added, and themixture was heated at 100° C. with stirring under nitrogen. After 22hours, additional 1-fluoro-2-nitrobenzene (350 mg) was added and heatingwas continued for 14 hours longer. The mixture was cooled to 40° C.,diluted with water (400 mL), and aqueous 10% HCl (25 mL) was added tobring the pH ˜3-4. The mixture was extracted with CHCl₃ (4×200 mL). Thecombined extract was concentrated under vacuum to a residue that waspurified by chromatography (SiO₂, eluted with hexanes-ethyl acetate,100:0-50:50-0:100) to provide the title compound: ¹H NMR (300 MHz,CDCl₃) δ ppm 1.48 (s, 9H), 2.34-2.55 (m, 1H), 2.73-2.90 (m, 1H),3.20-3.42 (m, 2H), 3.55-3.82 (m, 4H), 3.93-4.12 (m, 1H), 7.13-7.23 (m,2H), 7.45-7.55 (m, 1H), 7.74 (dd, J=7.9, 1.6 Hz, 1H).

Example 22D tert-butyl6-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,5]benzodiazepine-3(4H)-carboxylate

The product of Example 22C (658 mg, 1.801 mmol) was dissolved inmethanol (50 mL) and 10% Pd/C (52 mg) was added. The flask was evacuatedand purged with nitrogen (3 cycles) and then with hydrogen (3 cycles),and the reaction was stirred at room temperature under hydrogen (1 atm)for 7 hours. The flask was evacuated and purged with nitrogen (3cycles), and the reaction mixture was filtered through a pad ofdiatomaceous earth. The filtrate was concentrated under vacuum, and theresidue was dissolved in tetrahydrofuran (25 mL).O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (680 mg, 1.788 mmol) and diisopropylethylamine (1mL) were added, and the mixture was stirred at room temperature for 14hours and then concentrated under vacuum. The residue was purified bychromatography (SiO₂, eluted with hexanes-ethyl acetate, 100:0-50:50) toprovide the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.48 (s, 9H),2.18 (d, J=13.5 Hz, 1H), 2.74 (dd, J=13.3, 6.9 Hz, 1H), 2.88-3.30 (m,5H), 4.01-4.19 (m, 2H), 6.93-6.98 (m, 1H), 7.01-7.10 (m, 2H), 7.16 (s,1H), 7.17-7.24 (m, 1H); MS (DCI) m/z 318 (M+H)⁺.

Example 22E3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,5]benzodiazepin-6(7H)-one

Formalin solution (0.3 mL, 3.92 mmol) was added to a solution of theproduct of Example 22D (150 mg, 0.473 mmol) in 88% formic acid (4 mL),and the solution was stirred at 100° C. under nitrogen for 30 minutes.The mixture was cooled to room temperature and concentrated undervacuum. The residue was purified by chromatography (SiO₂, eluted withCH₂Cl₂-methanol-15 M NH₄OH, 90:10:1) to provide the title compound: ¹HNMR (500 MHz, DMSO-d₆/D₂O) δ ppm 2.05 (d, J=12.8 Hz, 1H), 2.66 (dd,J=13.6, 7.2 Hz, 1H), 2.90 (s, 3H), 3.08-3.19 (m, 2H), 3.32-3.39 (m, 2H),3.53 (t, J=11.0 Hz, 2H), 3.57-3.67 (m, 1H), 7.00-7.04 (m, 1H), 7.08-7.13(m, 1H), 7.13-7.18 (m, 1H), 7.18-7.24 (m, 1H); MS (DCI) m/z 232 (M+H)⁺.

Example 22F3-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine

Solid LiAlH₄ (100 mg, 2.63 mmol) was added to a stirred solution of theproduct of Example 22E (72 mg, 0.311 mmol) in tetrahydrofuran (10 mL) atroom temperature. The resulting mixture was heated at reflux undernitrogen for 2 hours, then cooled in ice and quenched by successiveaddition of ethyl acetate (4 mL), water (0.1 mL), 15% NaOH (0.1 mL) andwater (0.3 mL). The mixture was filtered through a pad of diatomaceousearth with an ethyl acetate (25 mL total) rinse. The filtrate wasconcentrated under vacuum to provide the title compound, sufficientlypure for use in the next step: ¹H NMR (300 MHz, CDCl₃) δ ppm 2.06-2.20(m, 2H), 2.25-2.42 (m, 2H), 2.37 (s, 3H), 2.62 (d, J=9.5 Hz, 1H),2.77-2.87 (m, 1H), 3.08 (dt, J=11.6, 3.1 Hz, 1H), 3.18 (ddd, J=12.2,5.3, 2.8 Hz, 1H), 3.22-3.33 (m, 1H), 3.64-3.75 (m, 2H), 6.53 (dd, J=7.5,2.0 Hz, 1H), 6.76 (td, J=7.4, 1.8 Hz, 1H), 6.83 (td, J=7.4, 1.8 Hz, 1H),6.92 (dd, J=7.5, 1.6 Hz, 1H); MS (DCI) m/z 218 (M+H)⁺.

Example 22G7-(4-bromobenzyl)-3-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine

Sodium triacetoxyborohydride (200 mg, 0.944 mmol) was added to anice-cooled solution of 4-bromobenzaldehyde (122 mg, 0.659 mmol) and theproduct of Example 22F (63 mg, 0.290 mmol) in tetrahydrofuran (5 mL). Afew drops of 10% HCl (aq) were added, and the mixture was allowed towarm to room temperature. After 5 hours, acetic acid (2 mL) andadditional sodium triacetoxyborohydride (200 mg, 0.944 mmol) were added,and the mixture was stirred an additional 15 hours. The reaction mixturewas concentrated under vacuum, and the residue was purified by flashchromatography (SiO₂, eluted with CH₂Cl₂, then CH₂Cl₂-methanol-15 MNH₄OH, 95:5:0.5-90:10:1) to provide the title compound: ¹H NMR (300 MHz,CD₃OD) δ ppm 1.62 (tt, J=15.3, 5.3, 2.6 Hz, 1H), 1.84-2.00 (m, 1H), 2.33(t, J=10.9 Hz, 1H), 2.42-2.51 (m, 1H), 2.43 (s, 3H), 2.77 (dt, J=10.7,2.0 Hz, 1H), 2.85 (ddd, J=11.1, 5.2, 3.6 Hz, 1H), 2.89-3.04 (m, 2H),3.13 (dt, J=11.9, 2.8 Hz, 1H), 3.30 (s, 1H), 3.45 (td, J=11.3, 2.8 Hz,1H), 4.22 (d, J=15.1 Hz, 1H), 4.46 (d, J=15.1 Hz, 1H), 6.77-6.96 (m,4H), 7.27 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H); MS (DCI) m/z386/388 (M+H)⁺.

Example 233-benzyl-6-(4-bromo-3-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (149.5 mg, 0.51 mmol) and4-bromo-3-fluorobenzaldehyde (155.2 mg, 0.77 mmol) were processedaccording to the procedure for Example 17 and purified by preparativeHPLC according to the method in Example 9 to give the title compound asthe tris-trifluoroacetic acid salt: ¹H NMR (500 MHz, pyridine-d₅) δ ppm2.52 (dt, J=10.8, 3.4 Hz, 1H) 2.59-2.70 (m, 3H), 2.92 (d, J=10.7 Hz,1H), 2.99 (d, J=11.0 Hz, 1H), 3.31-3.41 (m, 2H), 3.45-3.47 (m, 1H),3.56-3.64 (m, 2H), 3.74-3.80 (m, 3H), 4.11 (d, J=13.1 Hz, 1H), 6.94-6.95(m, 1H), 7.03 (t, J=7.3 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.16 (d, J=7.0Hz, 1H), 7.32-7.36 (m, 3H), 7.39-7.42 (m, 2H), 7.54-7.55 (m, 2H),7.57-7.58 (m, 1H); MS (DCI/NH₃) m/z 480 (M+H)⁺. Elemental analysis iscalculated for C₂₆H₂₇BrFN₃.3 TFA: C, 46.73; H, 3.68; N, 5.11. Found: C,47.07; H, 3.81; N, 5.23.

Example 243-benzyl-6-(3,5-difluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (99.6 mg, 0.34 mmol) and3,5-difluorobenzaldehyde (91.7 mg, 0.65 mmol) were processed accordingto the procedure for Example 17 and purified by preparative HPLC usingthe method described in Example 9 to give the title compound as thetris-trifluoroacetic acid salt: ¹H NMR (300 MHz, benzene-d₆) δ ppm1.71-1.74 (m, 1H), 2.13-2.23 (m, 2H), 2.35 (d, J=12.8 Hz, 1H) 2.86-2.89(m, 2H), 2.95-3.04 (m, 2H), 3.15-3.23 (m, 2H), 3.30-3.52 (m, 3H), 3.65(d, J=12.8 Hz, 1H), 4.44 (d, J=13.1 Hz, 1H), 6.33-6.39 (m, 2H), 6.53(dd, J=7.3, 0.9 Hz, 1H), 6.64-6.65 (m, 2H), 6.73 (td, J=7.5, 0.9 Hz,1H), 7.02-7.07 (m, 2H), 7.14-7.18 (m, 2H), 7.33-7.34 (m, 2H); MS(DCI/NH₃) m/z 420 (M+H)⁺. Elemental analysis is calculated forC₂₆H₂₇F2N₃.3.45 TFA: C, 48.61; H, 3.78; N, 5.17. Found: C, 48.65; H,3.75; N, 5.28.

Example 253-benzyl-6-(3,4-difluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (102.4 mg, 0.35 mmol) and3,4-difluorobenzaldehyde (121.3 mg, 0.85 mmol) were processed accordingto the procedure for Example 17 and purified by preparative HPLC usingthe method described in Example 4 to give the title compound: ¹H NMR(500 MHz, benzene-d₆) δ ppm 2.17 (td, J=10.2, 3.7 Hz, 1H), 2.26 (d,J=9.9 Hz, 1H), 2.31-2.40 (m, 2H), 2.50-2.52 (m, 1H) 2.59-2.64 (m, 2H),3.05-3.19 (m, 5H), 3.35-3.41 (m, 2H), 3.54 (d, J=13.1 Hz, 1H), 3.97 (d,J=12.8 Hz, 1H), 6.69-6.72 (m, 2H), 6.75 (d, J=7.9 Hz, 1H), 7.03-7.07 (m,1H), 7.11-7.19 (m, 2H), 7.23 (t, J=7.6 Hz, 1H), 7.37 (d, J=7.3 Hz, 2H);MS (DCI/NH₃) m/z 420 (M+H)⁺. Elemental analysis is calculated forC₂₆H₂₇F2N₃: C, 74.44; H, 6.49; N, 10.02. Found: C, 74.65; H, 6.12; N,9.99.

Example 263-benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepineExample 26A methyl 4-benzylpiperazinyl-2-acetate

A solution of trityl chloride (37.6 g, 132 mmol) in CH₂Cl₂ (188 mL) wasadded dropwise over 1 hour to an ice-cooled solution ofN-benzylethane-1,2-diamine (20.0 g, 133 mmol) and triethylamine (19.6mL, 140 mmol) in acetonitrile (25 mL). The mixture was allowed to warmto room temperature over 1 hour and the precipitated solids were removedby filtration and washed with CH₂Cl₂ (25 mL). The combined filtrate wasconcentrated under vacuum. The residue (64.11 g) was combined withacetonitrile (320 mL) and stirred vigorously as solid K₂CO₃ (36.8 g, 266mmol) and KI (0.78 g, 4.70 mmol) were added. Finally, (E)-methyl4-bromocrotanoate (Aldrich, 28.0 g, 133 mmol) was added, followed by anacetonitrile (10 mL) rinse, and the suspension was stirred at roomtemperature for 13 hours. The mixture was filtered, and the cake rinsedwith CH₃CN (60 mL) and then with CH₂Cl₂ (100 mL). The filtrate wasconcentrated under vacuum at a bath temperature of 55° C. to leave alight amber semisolid (72.4 g). This material was dissolved in methanol(100 mL) and a solution of HCl in dioxane (4 M, 40 mL) was added. Theresulting solution was heated at reflux for 90 minutes, then cooled toroom temperature and concentrated under vacuum. The residue was dilutedwith water (250 mL) and made acidic (pH ˜3) by the addition of 10% HCl(10 mL). The mixture was washed with ethyl acetate (2×120 mL), and theaqueous phase was made basic (pH˜9) by cautious addition of solid K₂CO₃(22 g), followed by 25% aqueous NaOH (10 mL). The mixture was extractedwith CHCl₃ (3×110 mL) and the combined organic phase was washed withsaturated brine, dried over Na₂SO₄ and concentrated under vacuum toleave the title compound of sufficient purity for use in the nextreaction: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.85 (dd, J=11.1, 9.9 Hz, 1H),2.11 (ddd, J=11.5, 9.1, 4.8 Hz, 1H), 2.32-2.45 (m, 2H), 2.69-2.77 (m,2H), 2.86-2.99 (m, 2H), 3.14-3.26 (m, 1H), 3.49 (s, 2H), 3.67 (s, 3H),7.23-7.35 (m, 5H); MS (DCI) m/z 249 (M+H)⁺.

Example 26B 2-(4-benzyl-1-(2-nitrophenyl)piperazin-2-yl)acetic acid

The product of Example 26A (5.0 g, 20.14 mmol), K₂CO₃ (10.02 g, 72.5mmol), 1-fluoro-2-nitrobenzene (2.84 g, 20.14 mmol) and 18-crown-6 (0.25g, 0.946 mmol) were combined with acetonitrile (72 mL) and water (18mL), and the mixture was heated at 100° C. under nitrogen for 29 hours.The reaction mixture was cooled to room temperature and concentratedunder vacuum. The aqueous residue was diluted with water (150 mL) andwashed with CH₂Cl₂ (100 mL). The aqueous phase was made acidic (pH ˜4)by cautious addition of 10% aqueous HCl (approximately 40 mL), thenextracted with CH₂Cl₂ (3×100 mL). The combined organic phases were dried(MgSO₄) and concentrated to provide the title compound of sufficientpurity for the next step: ¹H NMR (300 MHz, CD₃OD) δ ppm 2.29 (d, J=5.6Hz, 2H), 2.90-3.31 (m, 3H), 3.36-3.44 (m, 1H), 3.50-3.62 (m, J=13.9, 1.2Hz, 1H), 3.79-3.90 (m, 1H), 4.20-4.36 (m, 2H), 7.41 (t, J=7.7 Hz, 1H),7.45-7.58 (m, 6H), 7.64 (td, J=7.7, 1.6 Hz, 1H), 7.73 (dd, J=7.9, 1.6Hz, 1H); MS (DCI) m/z 365 (M+H)⁺.

Example 26C3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,5]benzodiazepin-6(7H)-one

Platinum on carbon (5%, 30 mg) was added to a solution of the product ofExample 26B (0.67 g, 1.88 mmol) in methanol (100 mL). The reaction flaskwas evacuated and purged with nitrogen (5 cycles) and then with hydrogen(5 cycles), and the suspension was stirred under hydrogen (1 atm) for 18hours. The reaction flask was evacuated and purged with nitrogen (5cycles), and the mixture was filtered through diatomaceous earth withethyl acetate (50 mL) and methanol (50 mL) rinses. The filtrate wasconcentrated under vacuum and the residue was dissolved inN,N-dimethylformamide (8 mL).O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (720 mg, 1.89 mmol) and diisopropylethylamine (0.395mL, 2.262 mmol) were added, and the solution was stirred at roomtemperature for 3 hours. The mixture was diluted with water (50 mL) andextracted with ethyl acetate (2×50 mL). The combined extracts werewashed successively with 1 N NaOH (50 mL) and brine (40 mL), and thenconcentrated under vacuum. The residue was purified by flashchromatography (SiO₂ eluted with CH₂Cl₂—CH₃OH, 100:0-95:5) to providethe title compound: ¹H NMR (300 MHz, CD₃OD) δ ppm 1.98 (dd, J=13.4, 1.2Hz, 1H), 2.27 (dt, J=11.4, 3.1 Hz, 1H), 2.40 (t, J=10.9 Hz, 1H), 2.67(dd, J=13.2, 7.5 Hz, 1H), 2.82-2.89 (m, 1H), 2.89-2.97 (m, 1H),3.01-3.09 (m, 1H), 3.22 (dd, J=11.5, 2.7 Hz, 1H), 3.35-3.44 (m, 1H),3.61 (s, 2H), 6.98 (dd, J=8.1, 1.7 Hz, 1H), 7.03 (td, J=7.3, 1.7 Hz,1H), 7.10-7.22 (m, 2H), 7.25-7.39 (m, 5H); MS (DCI) m/z 308 (M+H)⁺.

Example 26D3-benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine

Solid LiAlH₄ (180 mg, 4.74 mmol) was added at room temperature to astirring solution of the product of Example 26C (280 mg, 0.911 mmol) intetrahydrofuran (10 mL).

The resulting mixture was stirred at room temperature under nitrogen for12 hours, then heated at 60° C. for 1 hour. The reaction mixture wascooled in ice and quenched by successive addition of ethyl acetate (4mL), water (0.18 mL), 15% NaOH (0.18 mL) and water (0.54 mL). Themixture was filtered through diatomaceous earth with an ethyl acetate(25 mL) rinse. The filtrate was concentrated and the residue waspurified by preparative HPLC (30×100 mm, C18, Waters XBridge™ columneluted with 0.1 M (NH₄)₂CO_(3(aq))-methanol (95:5-10:90) over 18minutes) to provide the title compound: ¹H NMR (400 MHz, CD₃OD) δ ppm1.53-1.63 (m, 1H), 1.94-2.06 (tddd, J=12.0, 12.0, 6.1, 3.2, 3.1 Hz, 1H),2.29 (t, J=10.4 Hz, 1H), 2.37 (td, J=10.8, 3.1 Hz, 1H), 2.63 (ddd,J=10.5, 2.6, 2.2 Hz, 1H), 2.85 (dq, J=11.0, 2.7 Hz, 1H), 2.90-3.01 (m,2H), 3.09 (ddd, J=12.2, 5.2, 2.7 Hz, 1H), 3.21 (td, J=11.1, 2.9 Hz, 1H),3.53 (td, J=12.1, 1.5 Hz, 1H), 3.58 (s, 2H), 6.62 (dd, J=7.6, 1.5 Hz,1H), 6.73 (td, J=7.6, 1.7 Hz, 1H), 6.80 (td, J=7.6, 1.7 Hz, 1H), 6.89(dd, J=7.9, 1.5 Hz, 1H), 7.23-7.29 (m, 1H), 7.29-7.39 (m, 4H); MS (ESI)m/z 294 (M+H)⁺.

Example 271-(3-benzyl-2,3,4,4a,5,6-hexahydropyrazino[1,2-a][1,5]benzodiazepin-7(1H)-yl)-2-(4-chlorophenyl)ethanone

To a solution of the product of Example 26 (40 mg, 0.136 mmol) in CH₂Cl₂(4 mL) was added 2-(4-chlorophenyl)acetyl chloride (118 mg, 0.624 mmol),and the solution was stirred at room temperature for 2 hours and thenconcentrated under vacuum. The residue was crystallized from ethanol (4mL) and water (0.2 mL) to provide the title compound: ¹H NMR (400 MHz,pyridine-d₅) δ ppm 1.33-1.39 (m, 1H), 1.44-1.63 (m, 1H), 2.17 (t, J=11.9Hz, 1H), 2.24-2.43 (m, 1H), 2.64-2.79 (m, 2H), 2.82-2.90 (m, 1H),2.92-3.03 (m, 1H), 3.07-3.30 (m, 2H), 3.34-3.58 (m, 2H), 3.56-3.73 (m,2H), 4.32-4.56 (m, 1H), 6.86-7.20 (m, 5H), 7.23-7.52 (m, 8H); MS (DCI)m/z 446/448 (M+H)⁺. Elemental analysis is calculated for C₂₇H₂₈N₃OCl HCl0.24 EtOH 0.3H₂O: C, 66.17; H, 6.26; N, 8.43. Found: C, 66.03; H, 6.22;N, 8.38.

Example 283-benzyl-6-(pyridin-3-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (106.8 mg, 0.36 mmol) and3-pyridinecarboxaldehyde (66.1 mg, 0.62 mmol) were processed accordingto the procedure for Example 17 and purified by preparative HPLC usingthe method described in Example 4 to give the title compound: ¹H NMR(500 MHz, pyridine-d₅) δ ppm 2.32 (dt, J=10.2, 3.7 Hz, 1H), 2.37 (t,J=10.1 Hz, 1H), 2.57 (dd, J=13.4, 3.4 Hz, 1H), 2.68-2.72 (m, 2H),2.76-2.78 (m, 2H), 3.23-3.34 (m, 3H), 3.50-3.62 (m, 4H), 3.77 (d, J=13.1Hz, 1H), 4.05 (d, J=13.1 Hz, 1H), 6.95-7.01 (m, 2H), 7.11 (d, J=6.1 Hz,1H), 7.26 (dd, J=7.6, 4.6 Hz, 1H), 7.32-7.34 (m, 2H), 7.39-7.42 (m, 2H),7.74-7.76 (m, 1H), 8.69 (dd, J=4.7, 1.4 Hz, 1H), 8.85 (d, J=1.8 Hz, 1H);MS (DCI/NH₃) m/z 385 (M+H)⁺. Elemental analysis is calculated forC₂₅H₂₈N₄.0.25H₂O: C, 77.19; H, 7.38; N, 14.40. Found: C, 77.24; H, 7.30;N, 14.34.

Example 293-benzyl-6-(pyridin-2-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (120.9 mg, 0.41 mmol) and2-pyridinecarboxaldehyde (75.8 mg, 0.71 mmol) were processed accordingto the procedure for Example 17 and purified by preparative HPLC usingthe method described in Example 9 to give the title compound as thetetra-trifluoroacetic acid salt: ¹H NMR (400 MHz, pyridine-d₅) δ ppm2.46-2.53 (m, 1H) 2.69 (t, J=10.5 Hz, 1H), 2.88-3.03 (m, 4H), 3.28-3.40(m, 2H), 3.57-3.59 (m, 1H), 3.73-3.81 (m, 2H), 4.09-4.15 (m, 2H), 4.37(d, J=12.8 Hz, 1H), 6.91-6.93 (m, 1H), 6.98-7.02 (m, 1H), 7.16-7.18 (m,1H), 7.27 (dd, J=7.6, 1.5 Hz, 1H), 7.31-7.35 (m, 2H), 7.38-7.42 (m, 2H),7.53-7.54 (m, 2H), 7.62-7.68 (m, 2H), 8.65-8.67 (m, 1H); MS (DCI/NH₃)m/z 385 (M+H)⁺. Elemental analysis is calculated for C₂₅H₂₈N₄.4 TFA: C,47.15; H, 3.84; N, 6.67. Found: C, 47.44; H, 4.01; N, 6.80.

Example 303-benzyl-6-(pyridin-4-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (122.4 mg, 0.42 mmol) and4-pyridinecarboxaldehyde (80.3 mg, 0.75 mmol) were processed accordingto the procedure for Example 17 and purified by preparative HPLC usingthe method described in Example 4 to give the title compound: ¹H NMR(500 MHz, pyridine-d₅) δ ppm 2.34 (dt, J=10.2, 3.8 Hz, 1H), 2.41 (t,J=9.9 Hz, 1H), 2.34 (dd, J=13.4, 3.1 Hz, 1H), 2.68-2.72 (m, 2H),2.78-2.80 (m, 1H), 3.25-3.34 (m, 3H), 3.53-3.61 (m, 4H), 3.75 (d, J=12.8Hz, 1H), 4.06 (d, J=13.1 Hz, 1H), 6.97-7.03 (m, 2H), 7.12 (dd, J=7.3,1.5 Hz, 1H), 7.31-7.43 (m, 6H), 7.49-7.50 (m, 2H), 8.74-8.75 (m, 2H); MS(DCI/NH₃) m/z 385 (M+H)⁺.

Example 31(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(4-bromophenyl)methanone

The product of Example 2 (109.9 mg, 0.37 mmol) and 4-bromobenzoylchloride (152.3 mg, 0.69 mmol) were processed according to the procedurefor Example 4 to give the title compound: ¹H NMR (500 MHz, benzene-d₆) δppm (7:3 mixture of rotomers at 25° C.) 1.98-2.06 (m, 2.1H), 2.16-2.20(m, 0.3H), 2.38-2.39 (m, 1H), 2.56-2.58 (m, 1H), 2.71-2.73 (m, 1H),2.82-2.92 (m, 3.3H), 3.10-3.12 (m, 0.7H), 3.29-3.32 (m, 1H), 3.50 (d,J=12.8 Hz, 0.3H), 3.94 (d, J=12.5 Hz, 0.3H), 4.40 (d, J=13.4 Hz, 0.3H),4.56 (d, J=12.5 Hz, 0.3H), 4.79 (d, J=14.0 Hz, 0.7H), 5.02 (d, J=14.0Hz, 0.7H), 6.56-6.57 (m, 0.3H), 6.65-6.70 (m, 1H), 3.74-6.77 (m, 0.3H),6.85-6.89 (m, 2.1H), 7.05-7.21 (m, 8.6H), 7.31-7.36 (m, 0.7H); MS(DCI/NH₃) m/z 476 (M+H)⁺. Elemental analysis is calculated forC₂₆H₂₆BrN₃O.0.15H₂O: C, 65.18; H, 5.53; N, 8.77. Found: C, 64.91; H,5.22; N, 8.62.

Example 323-benzyl-6-[(6-methylpyridin-3-yl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (102.9 mg, 0.35 mmol) and 5-formyl-2-picoline(68.4 mg, 0.57 mmol) were processed according to the procedure forExample 17 and purified by preparative HPLC using the method describedin Example 4 to give the title compound: ¹H NMR (500 MHz, pyridine-d₅) δppm 2.32 (dt, J=10.2, 3.7 Hz, 1H), 2.37 (t, J=10.1 Hz, 1H), 2.53-2.58(m, 4H), 2.68-2.73 (m, 2H), 2.76-2.79 (m, 2H), 3.26-3.35 (m, 3H),3.50-3.59 (m, 4H), 3.80 (d, J=13.1 Hz, 1H), 4.06 (d, J=13.1 Hz, 1H),6.96-7.01 (m, 2H), 7.11-7.13 (m, 2H), 7.30-7.34 (m, 2H), 7.39-7.42 (m,2H), 7.48-7.49 (m, 2H), 7.65 (dd, J=7.6, 2.1 Hz, 1H), 8.71 (d, J=1.8 Hz,1H); MS (DCI/NH₃) m/z 399 (M+H)⁺. Elemental analysis is calculated forC₂₆H₃₀N₄: C, 78.35; H, 7.59; N, 14.06. Found: C, 78.02; H, 7.35; N,14.05.

Example 333-benzyl-6-(quinolin-3-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (99.7 mg, 0.34 mmol) andquinoline-3-carboxaldehyde (84.6 mg, 0.54 mmol) were processed accordingto the procedure for Example 17 and purified by preparative HPLC usingthe method described in Example 9 to give the title compound as thetris-trifluoroacetic acid salt: ¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.54(dt, J=10.8, 3.1 Hz, 1H), 2.66-2.79 (m, 2H), 2.75-2.79 (m, 1H), 2.96 (d,J=10.7 Hz, 1H), 3.02 (d, J=10.7 Hz, 1H), 3.31-3.34 (m, 1H), 3.39-3.43(m, 1H), 3.52-3.54 (m, 1H), 3.77-3.91 (m, 5H), 4.22 (d, J=13.1 Hz, 1H),6.95 (d, J=7.9 Hz, 1H), 7.03 (t, J=7.3 Hz, 1H), 7.19-7.20 (m, 1H),7.32-7.40 (m, 4H), 7.53-7.57 (m, 3H), 7.71-7.74 (m, 1H), 7.91 (d, J=7.9Hz, 1H), 8.24 (d, J=1.5 Hz, 1H), 8.36 (d, J=8.6 Hz, 1H), 9.23 (d, J=2.1Hz, 1H); MS (DCI/NH₃) m/z 435 (M+H)⁺. Elemental analysis is calculatedfor C₂₉H₃₀N₄.3.2 TFA.1.25H₂O: C, 51.73; H, 4.38; N, 6.82. Found: C,51.78; H, 4.48; N, 6.84.

Example 343-benzyl-6-[(6-chloropyridin-3-yl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (113.4 mg, 0.39 mmol) and6-chloronicotinaldehyde (81.7 mg, 0.58 mmol) were processed according tothe procedure for Example 17 and purified by preparative HPLC using themethod described in Example 9 to give the title compound as thetris-trifluoroacetic acid salt: ¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.84(dt, J=10.5, 3.8 Hz, 1H), 2.91-2.95 (m, 2H), 3.02-3.06 (m, 1H), 3.22 (d,J=10.4 Hz, 1H), 3.30 (d, J=11.0 Hz, 1H), 3.67-3.80 (m, 3H), 3.90-3.98(m, 2H), 4.05-4.13 (m, 3H), 4.44 (d, J=13.1 Hz, 1H), 7.32 (d, J=7.9 Hz,1H), 7.39 (t, J=7.3 Hz, 1H), 7.51 (dd, J=7.3, 1.5 Hz, 1H), 7.68-7.79 (m,5H), 7.89-7.90 (m, 2H), 8.11 (dd, 8.1, 2.3 Hz, 1H), 8.89 (d, 0.1=2.4 Hz,1H); MS (DCI/NH₃) m/z 419 (M+H)⁺. Elemental analysis is calculated forC₂₅H₂₇ClN₄.3 TFA: C, 48.92; H, 3.97; N, 7.36. Found: C, 49.03; H, 4.13;N, 7.40.

Example 353-benzyl-6-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (117.0 mg, 0.40 mmol) and6-(trifluoromethyl)pyridine-3-carboxaldehyde (102.9 mg, 0.59 mmol) wereprocessed according to the procedure for Example 17 and purified bypreparative HPLC using the method described in Example 4 to give thetitle compound: ¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.31-3.40 (m, 2H)2.58 (dd, J=13.2, 3.2 Hz, 1H), 2.68-2.71 (m, 2H), 2.77-2.79 (m, 1H),3.25-3.34 (m, 3H), 3.52-3.58 (m, 2H), 3.61-3.69 (m, 2H), 3.76 (d, J=13.1Hz, 1H), 4.05 (d, J=13.1 Hz, 1H), 6.97-7.03 (m, 2H), 7.13 (dd, J=7.3,1.2 Hz, 1H), 7.33-7.37 (m, 2H), 7.39-7.42 (m, 2H), 7.48-7.50 (m, 2H),7.72 (d, J=7.6, Hz, 1H), 7.95 (d, J=7.6, Hz, 1H), 8.87 (s, 1H); MS(DCI/NH₃) m/z 453 (M+H)⁺. Elemental analysis is calculated forC₂₆H₂₇F₃N₄.0.6H₂O: C, 67.40; H, 6.13; N, 12.09. Found: C, 67.30; H,6.04; N, 12.12.

Example 363-benzyl-6-(quinolin-4-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (155.3 mg, 0.53 mmol) andquinoline-4-carboxaldehyde (132.9 mg, 0.85 mmol) were processedaccording to the procedure for Example 17 and purified by preparativeHPLC using the method described in Example 4 to give the title compound:¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.33 (dt, J=10.2, 3.7 Hz, 1H), 2.40(t, J=10.1 Hz, 1H), 2.67-2.71 (m, 2H), 2.76-2.80 (m, 2H), 3.26-3.33 (m,2H), 3.37-3.40 (m, 1H), 3.50-3.57 (m, 2H), 3.85 (d, J=13.1 Hz, 1H),4.00-4.10 (m, 2H), 4.13 (d, J=12.8 Hz, 1H), 6.98-7.04 (m, 2H), 7.17 (dd,J=7.0, 1.2 Hz, 1H), 7.32-7.42 (m, 4H), 7.48-7.49 (m, 2H), 7.56-7.61 (m,2H), 7.73-7.76 (m, 1H), 8.36-8.41 (m, 2H), 9.05 (d, J=4.3 Hz, 1H); MS(DCI/NH₃) m/z 435 (M+H)⁺. Elemental analysis is calculated forC₂₉H₃₀N₄.0.35H₂O: C, 79.00; H, 7.02; N, 12.71. Found: C, 79.07; H, 7.01;N, 12.66.

Example 373-benzyl-6-(isoquinolin-4-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (152.2 mg, 0.52 mmol) andisoquinoline-4-carboxaldehyde (101.8 mg, 0.65 mmol) were processedaccording to the procedure for Example 17 and purified by preparativeHPLC using the method described in Example 9 to give the title compoundas the tris-trifluoroacetic acid salt: ¹H NMR (500 MHz, pyridine-d₅) δppm 2.47-2.52 (m, 1H), 2.58-2.62 (m, 1H), 2.65-2.74 (m, 2H), 2.87-2.89(m, 1H), 3.00-3.02 (m, 1H), 3.29-3.32 (m, 1H), 3.36-3.41 (m, 1H),3.47-3.48 (m, 1H), 3.72-3.77 (m, 2H), 3.85 (d, J=13.1 Hz, 1H), 3.95-4.02(m, 2H), 4.14 (d, J=13.1 Hz, 1H), 6.92-7.04 (m, 2H), 7.19-7.20 (m, 1H),7.33-7.34 (m, 2H), 7.39-7.42 (m, 2H), 7.51-7.53 (m, 2H), 7.63 (t, J=7.5Hz, 1H), 7.76 (t, J=7.5 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 8.43 (d, J=8.2Hz, 1H), 8.75 (s, 1H), 9.45 (s, 1H); MS (DCI/NH₃) m/z 435 (M+H)⁺.Elemental analysis is calculated for C₂₉H₃₀N₄.3TFA.0.2 H₂O: C, 53.88; H,4.31; N, 7.18. Found: C, 54.23; H, 4.70; N, 7.39.

Example 383-(4-fluorobenzyl)-2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one

2,3,4,4a,6,7-Hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one (680.0mg, 3.13 mmol, Example 2A) was dissolve in methanol (15 mL).4-Fluorobenzaldehyde (653.5 mg, 5.27 mmol) was added to the reaction andstirred at ambient temperature for 1 hour. Sodium cyanoborohydride(565.3 mg, 9.00 mmol) was then added, and the reaction was stirred atambient temperature for 17 hours. The reaction was then diluted with 1MNaOH (50 mL) and extract with dichloromethane (3×50 mL). The organiclayers were combined, and purified by silica gel chromatography (ethylacetate, R_(f) 0.40) to give the title compound: ¹H NMR (400 MHz,benzene-d₆) δ ppm 1.93 (td, J=11.0, 2.8 Hz, 1H), 2.42 (t, J=10.6 Hz,1H), 2.49-2.51 (m, 1H), 2.60 (dt, J=11.0, 2.6 Hz, 1H), 2.85 (td, J=11.2,2.9 Hz, 1H), 3.02-3.10 (m, 2H), 3.30 (d, J=13.2 Hz, 1H), 3.50 (dt,J=10.7, 2.3 Hz, 1H), 3.75 (dd, J=10.4, 2.8 Hz, 1H), 4.51 (dd, J=13.6,4.0 Hz, 1H), 6.72-6.73 (d, J=8.1 Hz, 1H), 6.75 (dd, J=7.3, 1.5 Hz, 1H),6.81-6.84 (m, 3H), 7.02-7.09 (m, 3H); MS (DCI/NH₃) m/z 326 (M+H)⁺.

Example 393-benzyl-6-[(6-bromopyridin-3-yl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (166.8 mg, 0.57 mmol) and6-bromonicotinaldehyde (154.9 mg, 0.83 mmol) were processed according tothe procedure for Example 17 and purified by preparative HPLC using themethod described in Example 9 to give the title compound as thetris-trifluoroacetic acid salt: ¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.46(td, J=10.4, 4.0 Hz, 1H), 2.50-2.58 (m, 2H), 2.64-2.68 (m, 1H),2.83-2.85 (m, 1H), 2.91-2.93 (m, 1H), 3.30-3.35 (m, 2H), 3.40-3.42 (m,1H), 3.50-3.58 (m, 2H), 3.67-3.70 (m, 2H), 3.74 (d, J=13.1 Hz, 1H), 4.07(d, J=13.1 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 7.02 (td, J=7.3, 0.9 Hz,1H), 7.13 (dd, J=7.3, 1.5 Hz, 1H), 7.32-7.35 (m, 2H), 7.39-7.42 (m, 2H),7.51-7.53 (m, 3H), 7.64 (dd, J=8.2, 2.4 Hz, 1H), 8.50 (d, J=2.1 Hz, 1H);MS (DCI/NH₃) m/z 463 (M+H)⁺. Elemental analysis is calculated forC₂₅H₂₇BrN₄.2.5 TFA: C, 48.14; H, 3.97; N, 7.49. Found: C, 48.02; H,4.08; N, 7.54.

Example 403-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 38 was dissolve in tetrahydrofuran (13 mL). Thereaction was chilled to 0° C. with an ice bath and LiAlH₄ (148.3, 3.91mmol) was added. The reaction was allowed to warm to ambienttemperature, then heated to reflux for 16 hours. The reaction mixturewas then treated with the dropwise addition of water (150 L), 15%NaOH(aq) (150 L) and water (450 μL). The resulting precipitate wasfiltered off. The filtrate was concentrated to give the title compound:¹H NMR (400 MHz, benzene-d₆) δ ppm 2.05 (td, J=10.7, 3.1 Hz, 1H), 2.28(t, J=10.2 Hz, 1H), 2.39-2.41 (m, 1H), 2.46-2.53 (m, 2H), 2.71-2.73 (m,1H), 2.77-2.80 (m, 1H), 2.91 (dt, J=11.0, 3.1 Hz, 1H), 3.02-3.05 (m,1H), 3.20-3.30 (m, 2H), 3.89 (d, J=12.8 Hz, 1H), 4.23 (d, J=12.5 Hz,1H), 6.64 (d, J=7.6 Hz, 1H), 6.84-6.89 (m, 3H), 7.07-7.13 (m, 4H); MS(DCI/NH₃) m/z 312 (M+H)⁺.

Example 41(3-benzyl-2,3,4,4a,5,6-hexahydropyrazino[1,2-a][1,5]benzodiazepin-7(1H)-yl)(4-bromophenyl)methanone

4-Bromobenzoyl chloride (80 mg, 0.365 mmol) was added to a solution ofthe product of Example 26 (80 mg, 0.273 mmol) in CH₂Cl₂(4 mL) at roomtemperature, and the mixture was stirred for 1 hour and thenconcentrated under vacuum. The residue was crystallized from ethanol (4mL) to provide the title compound: ¹H NMR (500 MHz, pyridine-d₅) δ ppm1.52 (d, J=16.2 Hz, 1H), 1.66-1.77 (m, 1H), 2.55 (t, J=10.4 Hz, 1H),2.62 (t, J=10.4 Hz, 1H), 2.93 (d, J=10.4 Hz, 1H), 3.11 (d, J=9.2 Hz,1H), 3.16 (d, J=11.0 Hz, 1H), 3.50 (t, J=10.5 Hz, 1H), 3.58 (d, J=13.4Hz, 1H), 3.62-3.75 (m, J=7.0 Hz, 1H), 3.79 (s, 2H), 4.30 (t, J=13.1 Hz,1H), 6.71-6.79 (m, 2H), 7.01 (d, J=7.6 Hz, 1H), 7.13-7.20 (m, 1H),7.29-7.40 (m, 5H), 7.43 (t, J=7.5 Hz, 2H), 7.68 (d, J=7.0 Hz, 2H); MS(DCI) m/z 476/478 (M+H)⁺. Elemental analysis is calculated forC₂₆H₂₆N₃OBr HCl 0.67 EtOH 0.6H₂O: C, 59.21; H, 5.86; N, 7.58. Found: C,59.16; H, 5.69; N, 7.59.

Example 423-benzyl-6-[(5-bromopyridin-2-yl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (103.1 mg, 0.35 mmol) and5-bromo-2-formylpyridine (100.6 mg, 0.54 mmol) were processed accordingto the procedure for Example 17 and purified by preparative HPLC usingthe method described in Example 9 to give the title compound as thetris-trifluoroacetic acid salt: ¹H NMR (500 MHz, pyridine-d₅) δ ppm2.36-2.43 (m, 1H), 2.49-2.53 (m, 1H), 2.69-2.72 (m, 1H), 2.76-2.87 (m,3H), 3.30-3.32 (m, 1H), 3.38-3.41 (m, 1H), 3.60-3.66 (m, 2H), 3.84-3.91(m, 3H), 4.17 (d, J=13.1 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 7.00 (t,J=7.3, 0.9 Hz, 1H), 7.19 (dd, J=7.3, 1.5 Hz, 1H), 7.31-7.34 (m, 2H),7.39-7.42 (m, 2H), 7.50-7.53 (m, 3H), 7.84 (dd, J=8.4, 2.3 Hz, 1H), 8.77(d, J=2.4 Hz, 1H); MS (DCI/NH₃) m/z 463 (M+H)⁺. Elemental analysis iscalculated for C₂₅H₂₇BrN₄.3.35 TFA.0.75H₂O: C, 44.33; H, 3.75; N, 6.52;F, 22.23. Found: C, 44.19; H, 3.57; N, 6.68; F, 22.20.

Example 43(3-benzyl-2,3,4,4a,5,6-hexahydropyrazino[1,2-a][1,5]benzodiazepin-7(1H)-yl)(pyridin-4-yl)methanone

The product of Example 26 (218 mg, 0.74 mmol) was combined withisonicotinoyl chloride hydrochloride (132 mg, 0.74 mmol) in CH₂Cl₂ (5mL), and the mixture was stirred at room temperature for 14 hours andthen concentrated under vacuum. The residue was purified by HPLC (30×100mm, C18, Waters XBridge™ column eluted with aqueous 0.1 M(NH)₄CO₃-methanol (95:5-5:95 over 18 minutes)) and then bychromatography on silica gel (CH₂Cl₂-methanol-15 M NH₄OH, 95:5:0.5) toprovide the title compound: ¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ ppm 1.74(s, 2H), 2.28-2.38 (m, 2H), 2.74 (d, J=10.4 Hz, 1H), 2.81-2.93 (m, 1.0Hz, 2H), 3.10-3.37 (m, 3H), 3.51-3.63 (m, 2H), 3.75-4.23 (m, 1H),6.60-6.73 (m, 2H), 6.97 (d, J=4.6 Hz, 2H), 6.98-7.02 (m, 1H), 7.13 (t,J=6.9 Hz, 1H), 7.20-7.28 (m, 1H), 7.29-7.38 (m, 4H), 8.36 (d, J=5.8 Hz,2H); MS (DCI) m/z 399 (M+H

Example 443-benzyl-7-[2-(4-chlorophenyl)ethyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine

A mixture of the product of Example 27 (99 mg, 0.205 mmol) intetrahydrofuran (9 mL) was stirred under nitrogen with ice cooling asalane-N,N-dimethylethylamine complex (Aldrich, 0.5 M in toluene, 2.0 mL,1.00 mmol) was added dropwise from a syringe. The mixture was stirredwith ice cooling for 30 minutes, and then it was allowed to warm to roomtemperature for 12 hours. The reaction mixture was quenched by additionof methanol (2 mL) and concentrated under vacuum. The residue waspurified by chromatography (SiO₂, eluted with hexanes-ethyl acetate,83:17) to provide the title compound: ¹H NMR (400 MHz, CD₃OD) δ ppm 1.53(dddd, J=15.2, 4.9, 2.8, 2.6 Hz, 1H), 1.79 (dddd, J=15.2, 11.9, 5.9, 3.4Hz, 1H), 2.19 (t, J=10.7 Hz, 1H), 2.29 (td, J=11.1, 2.8 Hz, 1H), 2.65(dt, J=10.3, 2.0 Hz, 1H), 2.74-2.91 (m, 5H), 2.98 (dt, J=11.5, 2.8 Hz,1H), 3.15-3.27 (m, 2H), 3.45-3.55 (m, 2H), 3.56-3.62 (m, 2H), 6.77-6.97(m, 4H), 7.14-7.23 (m, 4H), 7.24-7.40 (m, 5H); MS (ESI) m/z 432/434(M+H)⁺.

Example 453,7-dibenzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine

Solid LiAlH₄ (116 mg, 3.06 mmol) was added gradually to a mixture of theproduct of Example 41 (52.0 mg, 0.11 mmol) in tetrahydrofuran (6 mL) atroom temperature. The resulting mixture was heated at 60° C. undernitrogen for 3 hours, and then it was cooled in ice and quenched bysuccessive addition of ethyl acetate (1 mL), water (0.12 mL), 15% NaOH(0.12 mL), and water (0.36 mL). Diatomaceous earth (approximately 200mg) was added, and the resulting slurry was filtered with an ethylacetate (25 mL) rinse. The filtrate was concentrated under vacuum andthe residue was purified by preparative HPLC on a Phenomenex® Luna®C8(2) 5 μm 100 Å AXIA column (30×75 mm) eluted with acetonitrile:0.1%trifluoroacetic acid in water (10:90-95:5) to provide the title compoundas the bis-trifluoroacetic acid salt: ¹H NMR (500 MHz, pyridine-d₅) δppm 1.38-1.45 (m, 1H), 1.81-1.90 (m, 1H), 2.42 (t, J=10.4 Hz, 1H), 2.55(td, J=10.8, 2.6 Hz, 1H), 2.73-2.82 (m, 2H), 3.00-3.09 (m, 2H),3.11-3.18 (m, J=6.5, 6.5, 2.9 Hz, 1H), 3.45 (td, J=11.1, 2.1 Hz, 1H),3.50 (td, J=11.6, 1.8 Hz, 1H), 3.76 (s, 2H), 4.30 (d, J=15.6 Hz, 1H),4.49 (d, J=15.6 Hz, 1H), 6.90 (dd, J=7.8, 1.4 Hz, 1H), 6.94 (td, J=7.5,1.5 Hz, 1H), 6.98-7.05 (m, 2H), 7.29 (t, J=7.3 Hz, 1H), 7.32-7.46 (m,7H), 7.54 (d, J=7.0 Hz, 1H); MS (ESI) m/z 384 (M+H)⁺.

Example 463-benzyl-6-(4-iodobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 2 (153.3 mg, 0.52 mmol) and 4-iodobenzaldehyde(119.7 mg, 0.52 mmol) were processed according to the procedure forExample 17 and purified by preparative HPLC using the method describedin Example 9 to give the title compound as the tris-trifluoroacetic acidsalt: ¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.38-2.41 (m, 1H), 2.47 (t,J=10.1 Hz, 1H) 2.58-2.61 (m, 1H), 2.69-2.73 (m, 1H), 2.78-2.80 (m, 1H),2.58-2.87 (m, 1H), 3.31 (dd, J=6.9, 2.6 Hz, 1H), 3.40-3.42 (m, 2H),3.56-3.66 (m, 4H), 3.83 (d, J=13.1 Hz, 1H), 4.11 (d, J=13.1 Hz, 1H),6.95 (d, J=7.3, 1H), 7.02 (td, J=7.3, 1.2 Hz, 1H), 7.15 (dd, J=7.5, 1.4Hz, 1H), 7.23-7.24 (m, 2H), 7.31-7.36 (m, 2H), 7.39-7.42 (m, 2H),7.50-7.51 (m, 2H), 7.76-7.77 (m, 2H); MS (DCI/NH₃) m/z 510 (M+H)⁺.Elemental analysis is calculated for C₂₆H₂₈IN₃.3 TFA: C, 45.14; H, 3.67;N, 4.93. Found: C, 45.33; H, 3.63; N, 4.99.

Example 473-benzyl-7-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine

A solution of alane-N,N-dimethylethylamine complex in toluene (Aldrich,0.5 M, 1.5 mL, 0.750 mmol) was added to an ice-cooled mixture of theproduct of Example 41 (58.7 mg, 0.114 mmol) in tetrahydrofuran (5 mL).The mixture was stirred for 30 minutes, and then it was allowed to warmto room temperature for 50 minutes before being quenched by the additionof methanol (1.5 mL) and concentrated under vacuum. The residue wastaken up with 1 MNaOH (3 mL) and extracted with CH₂Cl₂ (2×10 mL). Thecombined organic phases were concentrated under vacuum, and the residuewas purified by purified by preparative HPLC on a Phenomenex® Luna®C8(2) 5 μm 100 Å AXIA column (30 mm×75 mm) eluting withacetonitrile:0.1% trifluoroacetic acid in water (10:90-95:5) to providethe title compound as the bis-trifluoroacetic acid salt: ¹H NMR (500MHz, pyridine-ds) δ ppm 1.38-1.47 (m, 1H), 1.77-1.89 (m, 1H), 2.40 (t,J=10.4 Hz, 1H), 2.54 (td, J=10.8, 2.6 Hz, 1H), 2.72 (ddd, J=11.3, 4.9,3.7 Hz, 1H), 2.80 (d, J=10.7 Hz, 1H), 3.00-3.09 (m, 2H), 3.09-3.16 (m,1H), 3.40-3.48 (m, 2H), 3.76 (s, 2H), 4.18 (d, J=15.6 Hz, 1H), 4.42 (d,J=15.6 Hz, 1H), 6.87 (dd, J=7.9, 1.2 Hz, 1H), 6.96 (td, J=7.4, 1.4 Hz,1H), 7.00 (dd, J=7.9, 1.8 Hz, 1H), 7.05 (td, J=7.5, 1.8 Hz, 1H), 7.30(d, J=8.5 Hz, 2H), 7.32-7.38 (m, 1H), 7.42 (t, J=7.3 Hz, 2H), 7.53 (d,J=8.2 Hz, 2H), 7.53-7.56 (m, 2H); MS (ESI) m/z 462/464 (M+H)⁺.

Example 483-benzyl-7-(pyridin-4-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine

A solution of alane-N,N-dimethylethylamine complex (Aldrich, 0.5 M intoluene, 3.1 mL, 1.55 mmol) was added dropwise with stirring to anice-cooled solution of the product of Example 43 (123 mg, 0.309 mmol) intetrahydrofuran (10 mL). The mixture was stirred under nitrogen as theice bath was allowed to expire over 2.5 hours. The reaction was quenchedby addition of methanol (2 mL) and concentrated under vacuum. Theresidue was purified by flash chromatography (SiO₂, eluted withCH₂Cl₂-methanol-15 MNH₄OH) and then by HPLC (30×100 mm, C18, WatersXBridge™ column eluting with aqueous 0.1 M (NH₄)₂CO₃-methanol(80:20-0:100 over 15 minutes)) to provide the title compound: ¹H NMR(300 MHz, CD₃OD) δ ppm 1.60 (ddt, J=15.3, 2.4 Hz, 1H), 1.85-2.03 (m,1H), 2.26 (t, J=10.7 Hz, 1H), 2.37 (td, J=11.1, 3.2 Hz, 1H), 2.70 (br d,J=10.7 Hz, 1H), 2.86-2.98 (m, 3H), 3.06 (dt, J=11.5, 2.8 Hz, 1H),3.25-3.35 (m, 1H), 3.55 (td, J=11.4, 2.2 Hz, 1H), 3.61 (s, 2H), 4.32 (d,J=16.7 Hz, 1H), 4.61 (d, J=16.7 Hz, 1H), 6.75 (dd, J=6.8, 2.4 Hz, 1H),6.78-6.92 (m, 2H), 6.94 (dd, J=7.1, 2.1 Hz, 1H), 7.24-7.39 (m, 5H), 7.42(d, J=5.9 Hz, 2H), 8.40 (d, J/=6.3 Hz, 2H); MS (ESI) m/z 385 (M+H)⁺.

Example 493-benzyl-7-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine

The product of Example 26 (241 mg, 0.821 mmol) was dissolved in 88%formic acid (5 mL), and 36% formalin solution (0.55 mL, 7.2 mmol) wasadded. The mixture was heated at 100° C. for 1 hour and then cooled toroom temperature. The mixture was concentrated under vacuum and theresidue purified by HPLC (30×100 mm, C18, Waters XBridge™ column clutingwith aqueous 0.1 M (NH₄)₂CO₃— methanol (80:20-0:100 over 15 minutes)) toprovide the title compound: ¹H NMR (300 MHz, CD₃OD) δ ppm 1.51 (dddd,J=15.3, 4.9, 2.7, 2.5 Hz, 1H), 1.76 (dddd, J=15.5, 12.0, 6.1, 4.1 Hz,1H), 2.34 (t, J=10.7 Hz, 1H), 2.42 (td, J=11.4, 3.4 Hz, 1H), 2.66-2.76(m, 2H), 2.79 (s, 3H), 2.80-2.85 (m, 1H), 2.85-2.93 (m, 1H), 3.02 (dt,J=11.5, 2.7 Hz, 1H), 3.20-3.29 (m, 1H), 3.50 (td, J=11.7, 3.1 Hz, 1H),3.61 (s, 2H), 6.82 (dd, J=7.8, 1.4 Hz, 1H), 6.84-7.01 (m, 3H), 7.22-7.40(m, 5H); MS (ESI) m/z 308 (M+H)⁺.

Example 504-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methyl]phenol

The product of Example 2 (101.8 mg, 0.35 mmol) and 4-hydroxybenzaldehyde(58.8 mg, 0.48 mmol) were processed according to the procedure forExample 17 and purified by preparative HPLC using the method describedin Example 9 to give the title compound as the tris-trifluoroacetic acidsalt: ¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.31-2.36 (m, 1H), 2.47 (t,J=10.1 Hz, 1H) 2.83-2.88 (m, 2H), 2.95-3.05 (m, 2H), 3.30-3.31 (m, 2H),3.57-3.60 (m, 1H), 3.65-3.68 (m, 2H), 4.07-4.15 (m, 2H), 4.31 (d, J=13.1Hz, 1H), 4.47 (d, J=13.1 Hz, 1H), 6.95-7.96 (m, 13H); MS (DCI/NH₃) m/z400 (M+H)⁺.

Example 519-benzyl-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-oneExample 51A methyl2-(4-benzyl-1-(3-nitropyridin-2-yl)piperazin-2-yl)acetate

The product of Example 26A (1.46 g, 4.70 mmol) and2-chloro-3-nitropyridine (0.746 g, 4.70 mmol) were combined withdiisopropylethylamine (0.82 mL, 4.7 mmol) and dimethyl sulfoxide (5 mL),and the mixture was heated under nitrogen at 95° C. for 13 hours. Themixture was cooled to room temperature and partitioned between water (50mL) and ethyl acetate (50 mL). The aqueous layer was extracted withCH₂Cl₂ (2×50 mL) and the extracts were combined with the ethyl acetatephase and concentrated under vacuum. The residue was purified bychromatography (SiO₂, eluted with hexanes-ethyl acetate 90:10-80:20) toprovide the title compound: ¹H NMR (300 MHz, CD₃OD) δ ppm 2.17 (td,J=11.7, 3.2 Hz, 1H), 2.33 (dd, J=11.7, 3.4 Hz, 1H), 2.75-2.84 (m, 3H),2.84-3.01 (m, 2H), 3.03-3.13 (m, 1H), 3.38-3.51 (m, 1H), 3.43 (d, J=13.2Hz, 1H), 3.47 (s, 3H), 3.59 (d, J=13.1 Hz, 1H), 6.84 (dd, J=8.1, 4.6 Hz,1H), 7.19-7.38 (m, 5H), 8.16 (dd, J=7.9, 1.6 Hz, 1H), 8.33 (dd, J=4.8,1.6 Hz, 1H); MS (ESI) m/z 371 (M+H)⁺.

Example 51B9-benzyl-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one

Platinum(IV) oxide (35 mg, 0.154 mmol) was added to a solution of theproduct of Example 51A (1.20 g, 2.92 mmol) in methanol (150 mL), and thesuspension was stirred under hydrogen (1 atm) for 1 hour. The reactionflask was evacuated and purged with nitrogen (4 cycles), and the mixturewas filtered through a pad of diatomaceous earth with a methanol (30 mL)rinse. A solution of 25% sodium methoxide in methanol (Aldrich, 1.83 g,8.47 mmol) was added to the filtrate, and the solution was stirred atreflux under nitrogen for 41 hours and then cooled to room temperature.The reaction mixture was concentrated under vacuum, and the residue waspurified by chromatography (SiO₂, eluted with CH₂Cl₂—CH₃OH, 95:5),followed by crystallization from ethanol (2 mL) to provide the titlecompound: ¹H NMR (300 MHz, CD₃OD) δ ppm 2.15 (dd, J=13.7, 3.0 Hz, 1H),2.22-2.32 (m, 1H), 2.31 (t, J=10.7 Hz, 1H), 2.75 (dd, J=13.7, 6.5 Hz,1H), 2.83-2.96 (m, 2H), 3.23 (td, J=12.7, 2.8 Hz, 1H), 3.51-3.59 (m,1H), 3.60 (s, 2H), 3.64-3.74 (m, 1H), 6.99 (dd, J=7.7, 5.0 Hz, 1H),7.22-7.40 (m, 6H), 8.08 (dd, J=4.8, 1.6 Hz, 1H); MS (DCI) m/z 309(M+H)⁺.

Example 529-benzyl-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine

Solid LiAlH₄ (255 mg, 6.72 mmol) was added gradually to a stirredsuspension of the product of Example 51B (337 mg, 1.093 mmol) intetrahydrofuran (25 mL). The resulting mixture was heated at refluxunder nitrogen for 1 hour, then cooled in ice and quenched by successiveaddition of ethyl acetate (3 mL), water (0.25 mL), 15% NaOH (0.25 mL)and water (0.75 mL). The gray slurry was filtered through diatomaceousearth with an ethyl acetate (30 mL total) rinse. The filtrate wasconcentrated under vacuum and the residue was purified by HPLC (30×100mm, C18, XBridge™ column eluting with aqueous 0.1 M (NH₄)₂CO₃— methanol,80:20-0:100 over 15 minutes) to provide the title compound: ¹H NMR (300MHz, CD₃OD) δ ppm 1.75-1.89 (m, 1H), 1.90-2.04 (m, 1H), 2.30 (dd,J=11.0, 9.0 Hz, 1H), 2.44 (ddd, J=10.9, 9.6, 3.2 Hz, 1H), 2.59 (ddd,J=10.9, 2.8, 1.2 Hz, 1H), 2.72-2.83 (m, 1H), 3.17 (ddd, J=12.5, 5.4, 3.7Hz, 1H), 3.26-3.34 (m, 1H), 3.33-3.53 (m, 3H), 3.52-3.63 (m, 2H), 6.73(dd, J=7.8, 4.7 Hz, 1H), 6.91 (dd, J=7.6, 1.5 Hz, 1H), 7.20-7.40 (m,5H), 7.61 (dd, J=4.9, 1.5 Hz, 1H); MS (ESI) m/z 295 (M+H)⁺.

Example 531-(9-benzyl-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl)-2-(4-chlorophenyl)ethanone

A solution of the product of Example 52 (135 mg, 0.367 mmol) in CH₂Cl₂(3 mL) was added to 4-chlorophenylacetyl chloride (Aldrich, 0.058 mL,0.38 mmol), and the resulting solution was stirred at room temperaturefor 45 minutes. Methanol (0.5 mL) was added and the mixture was stirredfor 10 minutes and then concentrated under vacuum. The residue wascrystallized from ethanol (4 mL) and water (0.2 mL) to provide the titlecompound as the HCl salt: ¹H NMR (400 MHz, pyridine-d₅) δ ppm 2.57-2.86(m, 3H), 2.92-3.31 (m, 2H), 3.32-3.59 (m, 7H), 4.29-4.66 (m, 2H),6.69-6.88 (m, 1H), 6.91-7.04 (m, 2H), 7.21 (d, J=8.2 Hz, 2H), 7.25 (d,J=7.3 Hz, 1H), 7.27-7.36 (m, J=7.3, 7.3 Hz, 3H), 7.37-7.44 (m, 2H),8.23-8.33 (m, 1H), one proton obscured by solvent; MS (ESI) m/z 447/449(M+H)⁺. Elemental analysis is calculated for C₂₆H₂₇N₄OCl.HCl.0.4H₂O: C,63.65; H, 5.92; N, 11.42. Found: C, 63.72; H, 5.75; N, 11.26.

Example 549-benzyl-5-[2-(4-chlorophenyl)ethyl]-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine

The product of Example 53 (44 mg, 0.1 mmol) was partitioned with CH₂Cl₂(25 mL) and 20% Na₂CO_(3(aq)) (5 mL). The organic layer was dried(Na₂SO₄) and concentrated under vacuum. The residue was dissolved intetrahydrofuran (3 mL) and cooled in ice under nitrogen. A solution ofalane-N,N-dimethylethylamine complex in toluene (Aldrich, 0.5 M, 1.0 mL,0.50 mmol) was added, and the turbid mixture warmed gradually to roomtemperature and stirred for 12 hours. Methanol (2 mL) was added, and themixture was concentrated under vacuum. The residue was partitionedbetween CH₂Cl₂ (5 mL) and 1 M NaOH (5 mL), and the organic phase wasapplied to a column of silica gel and eluted with hexanes-ethyl acetate(80:20-0:100) to provide the title compound: ¹H NMR (300 MHz, CD₃OD) δppm 1.61-1.87 (m, 2H), 2.07 (t, J=10.3 Hz, 1H), 2.23 (td, J=10.9, 3.2Hz, 1H), 2.61 (d, J=10.3 Hz, 1H), 2.74-2.82 (m, 1H), 2.81 (t, J=6.7 Hz,2H), 2.92-3.04 (m, 1H), 3.11-3.21 (m, 1H), 3.22-3.29 (m, 2H), 3.32-3.52(m, 3H), 3.54 (s, 2H), 6.85 (dd, J=7.7, 5.0 Hz, 1H), 7.08-7.16 (m, 3H),7.18-7.39 (m, 7H), 7.69 (dd, J=5.0, 1.4 Hz, 1H); MS (ESI) m/z 433/435(M+H)⁺.

Example 559-benzyl-5-methyl-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine

Formic acid (88%, 3 mL) was added to a solution of the product ofExample 52 (97 mg, 0.231 mmol) in CH₂Cl₂ (2 mL). Aqueous formalin (0.5mL, 6.5 mmol) was added, and the mixture was heated at 110° C. for 45minutes, then cooled to room temperature and concentrated under vacuum.The residue was purified by HPLC (30×100 mm XBridge™ column cluting withaqueous 0.1 M (NH₄)₂CO₃-methanol, 80:20-0:100 over 15 minutes) toprovide the title compound: ¹H NMR (300 MHz, CD₃OD) δ ppm 1.62-1.74 (m,1H), 1.77-1.91 (m, 1H), 2.23 (t, J=10.5 Hz, 1H), 2.39 (td, J=11.0, 3.1Hz, 1H), 2.70 (ddd, J=10.8, 2.4, 1.9 Hz, 1H), 2.79 (s, 3H), 2.80-2.88(m, 1H), 2.96 (ddd, J=11.1, 6.5, 4.4 Hz, 1H), 3.23-3.29 (m, 1H),3.32-3.40 (m, 2H), 3.50 (dt, J=12.9, 3.1 Hz, 1H), 3.59 (s, 2H), 6.87(dd, J=7.8, 4.7 Hz, 1H), 7.08 (dd, J=7.8, 1.4 Hz, 1H), 7.22-7.39 (m,5H), 7.71 (dd, J=4.9, 1.5 Hz, 1H); MS (ESI) m/z 309 (M+H)⁺.

Example 566-(4-bromobenzyl)-3-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 40 (385.7 mg, 1.24 mmol), was dissolved inmethanol (10 mL). 4-Bromobenzaldehyde (360.5 mg, 1.95 mmol) was added tothe reaction and stirred for 1 hour at ambient temperature. Sodiumcyanoborohydride (238.9 mg, 3.80 mmol) was then added, and the reactionwas stirred at ambient temperature for 20 hours. The reaction was thendiluted with 1 MNaOH (50 mL) and extracted with dichloromethane (3×50mL). The organic layers were combined, concentrated and purified bysilica gel chromatography (ethyl acetate/dichloromethane 1:1, R_(f)0.33) to give the title compound: ¹H NMR (500 MHz, pyridine-d₅) δ ppm2.31 (td, J=10.4, 3.4 Hz, 1H), 2.37 (t, J=9.9 Hz, 1H), 2.57 (dd, J=13.3,3.2 Hz, 1H), 2.67-2.76 (m, 3H), 3.24-3.35 (m, 3H), 3.45-3.57 (m, 4H),3.79 (d, J=12.8 Hz, 1H), 4.06 (d, J=13.1 Hz, 1H), 6.98 (d, J=7.9 Hz,1H), 7.02 (td, J=7.3, 0.9 Hz, 1H), 7.13-7.19 (m, 3H), 7.33-7.36 (m, 3H),7.40-7.43 (m, 2H), 7.54-7.56 (m, 2H); MS (DCI/NH₃) m/z 480 (M+H)⁺.Elemental analysis is calculated for C₂₆H₂₇BrFN₃: C, 65.00; H, 5.66; N,8.75. Found: C, 64.74; H, 5.51; N, 8.59.

Example 576-(4-bromobenzyl)-3-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepineExample 57A3-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 1 (148.7 mg, 0.47 mmol) was dissolved intetrahydrofuran (14 mL). The reaction was chilled to 0° C. with an icebath and lithium aluminum hydride (57.8 mg, 1.52 mmol) was added. Thereaction was allowed to warm to ambient temperature and stirred for 20hours. The reaction was diluted with ethyl acetate (2 mL), then water(60 μL), 15% NaOH (60 μL) and water (180 μL) were added dropwiseproducing a precipitate. The precipitate was filtered off and thefiltrated concentrated to give the title compound: MS (DCI/NH₃) m/z 218(M+H)⁺.

Example 57B6-(4-bromobenzyl)-3-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 57A (97.8 mg, 0.48 mmol) and 4-bromobenzaldehyde(128.8 mg, 0.70 mmol) were processed according to the procedure forExample 17 and purified by preparative HPLC as described in Example 9 togive the title compound as the tris-trifluoroacetic acid salt: ¹H NMR(500 MHz, pyridine-d₅) δ ppm 2 2.50 (dd, J=13.7, 3.4 Hz, 1H), 2.57 (dd,J=13.7, 4.1 Hz, 1H), 2.79 (s, 3H), 2.92 (td, J=11.6, 3.4 Hz, 1H), 3.14(t, J=11.0 Hz, 1H), 3.31-3.37 (m, 2H), 3.46-3.48 (m, 2H), 3.53-3.64 (m,4H), 4.14 (d, J=13.1 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 7.03 (td, J=7.4,1.1 Hz, 1H), 7.13 (dd, J=7.3, 1.5 Hz, 1H), 7.28-7.32 (m, 3H), 7.52-7.54(m, 2H); MS (DCI/NH₃) m/z 386 (M+H)⁺. Elemental analysis is calculatedfor C₂₀H₂₄BrN₃.3.35 TFA: C, 41.74; H, 3.59; N, 5.47. Found: C, 41.80; H,3.47; N, 5.55.

Example 58(9-benzyl-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl)(2,2,3,3-tetramethylcyclopropyl)methanone

O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (254 mg, 0.668 mmol) and2,2,3,3-tetramethylcyclopropanecarboxylic acid (95 mg, 0.668 mmol) wereadded to a solution of the product of Example 52 (164 mg, 0.45 mmol) anddiisopropylethylamine (0.16 mL, 0.89 mmol) in CH₂Cl₂ (5 mL). The mixturewas stirred at room temperature for 45 hours, and then concentratedunder vacuum. The residue was purified by preparative HPLC on aPhenomenex® Luna® C8(2) 5 μm 100 Å AXIA column (30×75 mm), eluting withmethanol:10 mM ammonium acetate in water (10:90-95:5) to provide thetitle compound: ¹H NMR (400 MHz, pyridine-d₅, 110° C.) δ ppm 0.90 (s,6H), 1.33 (s, 3H), 1.35 (s, 3H), 1.69 (q, J=6.1 Hz, 2H), 2.04 (s, 1H),2.03-2.13 (m, 1H), 2.40 (td, J=10.8, 2.9 Hz, 1H), 2.64 (d, J=11.0 Hz,1H), 2.78 (d, J=10.7 Hz, 1H), 3.33-3.44 (m, 1H), 3.43 (ddd, J=13.1,11.0, 3.0 Hz, 1H), 3.49 (s, 2H), 3.57-3.72 (m, 2H), 4.03-4.13 (m, 1H),6.80 (dd, J=7.5, 4.7 Hz, 1H), 7.22 (t, J=7.3 Hz, 1H), 7.27-7.33 (m,J=7.3, 7.3 Hz, 3H), 7.35-7.40 (m, 2H), 8.26 (dd, J=4.6, 1.8 Hz, 1H); MS(ESI) m/z 419 (M+H)⁺.

Example 599-benzyl-5-[(2,2,3,3-tetramethylcyclopropyl)methyl]-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine

A solution of alane-N,N-dimethylethylamine complex (Aldrich, 0.5 M intoluene, 1.4 mL, 0.70 mmol) was added to an ice-cooled solution of theproduct of Example 58 (59 mg, 0.141 mmol) in tetrahydrofuran (5 mL). Themixture was stirred with ice cooling under nitrogen for 90 minutes, andthen it was warmed to room temperature. After 4 hours, methanol (5 mL)was added, and the mixture was concentrated under vacuum. The residuewas purified by HPLC (30×100 mm XBridge™ column eluted with aqueous 0.1M (NH₄)₂CO₃— methanol, 80:20-0:100 over 15 minutes) to provide the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ ppm 0.95 (s, 3H), 0.96 (s, 3H), 1.08(s, 3H), 1.09 (s, 3H), 1.53-1.61 (m, 1H), 1.65-1.79 (m, 1H), 1.80-1.94(m, 1H), 2.16-2.29 (m, 1H), 2.33-2.52 (m, 1H), 2.57-2.74 (m, 1H),2.78-2.93 (m, 1H), 2.99 (dd, J=12.1, 6.3 Hz, 1H), 2.97-3.11 (m, 1H),3.07 (dd, J=13.4, 5.9 Hz, 1H), 3.24-3.73 (m, 6H), 6.77 (dd, J=7.5, 4.8Hz, 1H), 6.96 (dd, J=7.5, 1.6 Hz, 1H), 7.27-7.45 (m, 5H), 7.80 (dd,J=4.6, 1.4 Hz, 1H); MS (ESI) m/z 405 (M+H)⁺.

Example 601-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-(6-chloropyridin-3-yl)ethanone

The product of Example 2 (98.3 mg, 0.34 mmol) was dissolved indichloromethane (3 mL). (6-Chloropyridin3-yl)acetic acid (99.2 mg, 0.58mmol), 1-hydroxybenzotriazole hydrate (62.8 mg, 0.41 mmol), (13.8 mg,0.11 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (95.7 mg, 0.58 mmol) were added, and the reaction wasstirred at ambient temperature for 16 hours. The reaction wasconcentrated and purified by preparative HPLC using the method describedin Example 4 to give the title compound: ¹H NMR (300 MHz, methanol-d₄) δppm 2.09-2.23 (m, 4H), 2.40 (s, 3H), 3.19-3.45 (m, 5H), 4.36 (s, 2H),4.98 (s, 2H), 6.96-7.00 (m, 1H), 7.14 (s, 1H), 7.19-7.23 (m, 3H),7.61-7.65 (m, 2H) ppm; MS (DCI/NH₃) m/z 447 (M+H)⁺. Elemental analysisis calculated for C₂₆H₂₇ClN₄O.0.25H₂O: C, 69.17; H, 6.14; N, 12.41.Found: C, 69.11; H, 6.08; N, 12.55.

Example 61(+)-(4aS)-6-(4-bromobenzyl)-3-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 56 (298.3 mg, 0.96 mmol) was separated in toindividual enantiomers by SFC purification carried out using a modifiedBerger Instruments PrepSFC™ system. A manual version of the Bergersystem was integrated with a Gilson 232 autosampler for sample injectionand a Cavro MiniPrep™ pipettor customized for fraction collection atatmospheric pressure (Olson, J.; Pan, J.; Hochlowski, J.; Searle, P.;Blanchard, D. JALA 2002, 7, 69-74). Custom designed collection shoesallowed collection into 18×150 mm tubes and a methanol wash systemallows washing of shoes between fractions to maximize recovery and avoidcross-contamination of fractions. The system was controlled using SFCProNTo™ software (version 1.5.305.15) and an Abbott developed VisualBasic application for autosampler and fraction collector control. Theoutlet pressure was 100 bar, oven temperature at 35° C., and mobilephase flow rate at 40 mL/minute (Daicel/Chiral Technologies Chiralpak®AD-H column, 5-50% methanol:CO₂ 100 bar+0.1% diethylamine). Thepreparative SFC system was controlled using SFC ProNTo™ software(version 1.5.305.15) and custom software for autosampler and fractioncollector control. Fractions were collected based upon UV signalthreshold and on-line Thermo MSQ mass spectrometry was used formolecular mass confirmation, using ESI ionization in positive mode. Massspectra were acquired using a Navigator4.0 software and an Abbottdeveloped Visual Basic interface to communicate with SFC controllingsoftware. The first eluting isomer (retention time 15.29 minutes) wascrystallized from methanol. The stereochemistry of the first elutingisomer (S configuration) was determined by single crystal X-rayanalysis. [α]²⁰ _(D)=+ 20° (c 0.93, CH₂Cl₂).

Example 62(−)-(4aR)-6-(4-bromobenzyl)-3-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

Continued elution (retention time 19.05 minutes) of the procedure inExample 61 afforded the enantiomer of Example 61. The stereochemistry ofthe second eluting isomer (R configuration) was assigned based on thiscompound being the enantiomer of Example 61. [α]²⁰ _(D)=−19° (c 0.94,CH₂Cl₂).

Example 633-benzyl-6-[2-(6-chloropyridin-3-yl)ethyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 60 (74.4 mg, 0.17 mmol) was dissolved intetrahydrofuran (5 mL). The reaction was chilled to 0° C. with an icebath and the lithium aluminum hydride (25.3 mg, 0.25 mmol) was added.The reaction was allowed to warm to ambient temperature and stirred for4 hours. The reaction was diluted with ethyl acetate (2 mL), then water(25 μL), 15% NaOH (25 μL) and water (75 μL) were added dropwiseproducing a precipitate. The precipitate was filtered off, the filtratewas concentrated, and the residue was purified by preparative HPLC usingthe method described in Example 4 to give the title compound: ¹H NMR(500 MHz, pyridine-d₅) δ ppm 2.30-2.36 (m, 2H), 2.56-2.79 (m, 8H),3.23-3.31 (m, 3H), 3.51-3.56 (m, 2H), 3.84 (d, J=12.8 Hz, 1H), 4.12 (d,J=12.8 Hz, 1H), 6.96 (d, J=7.9, 1H), 7.02 (t, J=7.5 Hz, 1H), 7.32-7.35(m, 3H), 7.40-7.43 (m, 2H), 7.49-7.51 (m, 2H), 7.50-7.51 (m, 2H),7.56-7.58 (m, 2H), 8.42 (d, J=2.4 Hz, 1H); MS (DCI/NH₃) m/z 433 (M+H)⁺.

Example 645-(cyclopropylmethyl)-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepineExample 64A tert-butyl6-oxo-6,7,7a,8,10,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine-9(5H)-carboxylate

Diisopropylethylamine (3.03 mL, 17.34 mmol) was added to a mixture of2-chloro-3-nitropyridine (2.75 g, 17.34 mmol) and the product of Example22B (4.48 g, 17.34 mmol) in dimethyl sulfoxide (20 mL). The mixture washeated at 95° C. under nitrogen for 7 hours and then cooled to roomtemperature. Ice water (200 mL) was added, and the mixture was extractedwith ethyl acetate (2×100 mL). The organic phase was washed withsaturated brine (60 mL), dried (MgSO₄) and concentrated under vacuum toan oil (6.81 g). This material was dissolved in methanol (400 mL), andPtO₂ (25 mg, 0.11 mmol) was added. The flask was evacuated and purgedwith nitrogen (3 cycles) and then with hydrogen (3 cycles). Thesuspension was stirred under hydrogen (1 atm) for 54 hours. The flaskwas evacuated and purged with nitrogen (3 cycles) and the blacksuspension was filtered through diatomaceous earth with a methanol (2×10mL) rinse. Sodium methoxide (Aldrich, 25% in methanol, 12.01 g, 55.6mmol) was added to the filtrate, and the mixture was heated at refluxfor 41 hours. After cooling to room temperature, the reaction mixturewas concentrated under vacuum. The residue was purified bychromatography (SiO₂, eluted with methanol-CH₂Cl₂ (0:100-5:95), followedby crystallization from ethanol (10 mL) to provide the title compound:¹H NMR (300 MHz, CDCl₃) δ ppm 1.48 (s, 9H), 2.27-2.40 (m, 1H), 2.78 (dd,J=13.5, 5.9 Hz, 1H), 2.91-3.20 (m, 3H), 3.55-3.68 (m, 1H), 3.69-3.80 (m,1H), 3.99-4.19 (m, 2H), 6.95 (dd, J=7.7, 5.0 Hz, 1H), 7.23 (dd, J=7.7,1.4 Hz, 1H), 7.61 (s, 1H), 8.18 (dd, J=5.0, 1.8 Hz, 1H); MS (ESI) m/z319 (M+H)⁺.

Example 64B9-(4-fluorobenzoyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one

A solution of the product of Example 64A (0.50 g, 1.570 mmol) in CH₂Cl₂(3 mL) was stirred with ice cooling as trifluoroacetic acid (2 mL) wasadded over 1 minute. The resulting solution was stirred at 0° C. for 50minutes and then allowed to warm to room temperature for 1 hour. Themixture was concentrated under vacuum, and the residue was taken up in6% NaOH (12 mL) and CH₂Cl₂ (5 mL), and p-fluorobenzoyl chloride (0.45 g,2.8 mmol) was added. The mixture was stirred at room temperature for 13hours and then filtered through diatomaceous earth with a CHCl₃ (25 mL)rinse. The aqueous layer was extracted with CHCl₃ (2×25 mL) and thecombined extract was dried (Na₂SO₄) and concentrated under vacuum. Theresidue was purified by chromatography (SiO₂, CH₂Cl₂-methanol-15 MNH₄OH, 95:5:0.5) to provide the title compound: MS (DCI) m/z 341 (M+H)⁺.

Example 64C9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine

Solid LiAlH₄ (357 mg, 9.41 mmol) was added to a vigorously stirredsolution of the product of Example 64B (528 mg, 1.55 mmol) intetrahydrofuran (40 mL). The resulting gray suspension was heated atreflux under nitrogen for 1 hour and then cooled in ice. The reactionwas quenched by successive addition of ethyl acetate (5 mL), water (0.35ml), 15% NaOH (0.35 mL) and water (1.05 mL). The resulting slurry wasstirred for 10 minutes, filtered (tetrahydrofuran (15 mL) and ethylacetate (15 mL) rinse), and the filtrate was concentrated to provide thetitle compound, sufficiently pure for use in the next step: ¹H NMR (300MHz, CDCl₃) δ ppm 1.78-1.90 (m, 1H), 1.92-2.03 (m, 1H), 2.19-2.31 (m,1H), 2.44-2.62 (m, J=8.7 Hz, 2H), 2.72-2.85 (m, J=10.7 Hz, 1H), 3.26(ddd, J=12.1, 5.6, 3.8 Hz, 1H), 3.38-3.62 (m, 6H), 6.67 (dd, J=7.5, 4.5Hz, 1H), 6.74 (dd, J=7.5, 2.0 Hz, 1H), 6.94-7.06 (m, 2H), 7.28-7.39 (m,2H), 7.78 (dd, J=4.8, 1.6 Hz, 1H); MS (ESI) m/z 313 (M+H)⁺.

Example 64D5-(cyclopropylmethyl)-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine

Cyclopropanecarbonyl chloride (0.043 ml, 0.478 mmol) was added to asolution of the product of Example 64C (97 mg, 0.31 mmol) in CH₂Cl₂ (2.0mL). The mixture was stirred at room temperature for 2 hours and thenconcentrated under vacuum. The residue was taken up in 1 MNaOH (5 mL)and extracted with ethyl acetate (2×10 mL). The combined extract waswashed with saturated brine (5 mL), dried (Na₂SO₄) and concentratedunder vacuum. The residue was dissolved in tetrahydrofuran (5 mL) andstirred with alane-N,N-dimethylethylamine complex (Aldrich, 0.5 Mintoluene, 2.9 mL, 1.45 mmol) at room temperature for 90 minutes. Methanol(1 mL) was added followed by water (5 mL) and 25% NaOH (1 mL). Themixture was stirred at room temperature for 10 minutes, and the aqueousphase was separated and extracted with ethyl acetate (2×7 mL). Thecombined organic was washed with saturated brine (5 mL), dried (Na₂SO₄)and concentrated under vacuum. The residue was purified bychromatography (SiO₂ eluted with CH₂Cl₂—CH₃OH 95:5) and then by HPLC(30×100 mm, C18, Waters XBridge™ column eluted with aqueous 0.1 M(NH₄)₂CO₃—CH₃OH, 80:20-0:100 over 15 minutes) to provide the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ ppm 0.15-0.23 (m, 2H), 0.51-0.61 (m,2H), 0.94-1.06 (m, 1H), 1.66-1.80 (m, 1H), 1.80-1.95 (m, 1H), 2.19 (t,J=9.7 Hz, 1H), 2.42 (td, J=10.5, 3.1 Hz, 1H), 2.59 (d, J=10.9 Hz, 1H),2.74-2.84 (m, 1H), 2.95 (d, J=6.4 Hz, 2H), 3.22 (ddd, J=11.5, 6.1, 4.1Hz, 1H), 3.30-3.39 (m, 1H), 3.38-3.48 (m, 2H), 3.52 (d, J=6.4 Hz, 2H),3.61 (dt, J=12.5, 3.4 Hz, 1H), 6.75 (dd, J=7.8, 4.7 Hz, 1H), 6.95 (dd,J=7.8, 1.7 Hz, 1H), 6.97-7.05 (m, 2H), 7.32 (dd, J=8.5, 5.8 Hz, 2H),7.80 (dd, J=4.7, 1.7 Hz, 1H); MS (DCI) m/z 367 (M+H)⁺.

Example 655-(cyclobutylmethyl)-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepineExample 65Acyclobutyl[9-(4-fluorobenzyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl]methanone

A solution of the product of Example 64C (97 mg, 0.31 mmol) indichloromethane (2 mL) was added to cyclobutanecarbonyl chloride (0.048mL, 0.42 mmol). The resulting, turbid solution was stirred at roomtemperature for 12 hours, and then the reaction was quenched by theaddition of 20% Na₂CO₃ (1 mL). After 30 minutes, the mixture was madebasic (pH˜9) by addition of 1 MNaOH (˜0.2 mL), diluted with water (3 mL)and extracted with CHCl₃ (3×2 mL). The combined organic phases weredried over K₂CO₃ and concentrated: ¹H NMR (300 MHz, CD₃OD) δ ppm1.58-2.02 (m, 5H), 2.06-2.44 (m, 4H), 2.68-3.26 (m, 6H), 3.42-3.65 (m,3H), 3.96-4.47 (m, 2H), 6.82-7.11 (m, 3H), 7.17-7.58 (m, 3H), 8.08-8.32(m, 1H); MS (DCI) m/z 395 (M+H)⁺.

Example 65B5-(cyclobutylmethyl)-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine

A solution of alane-dimethylethylamine complex (0.5 M in toluene, 3.1mL, 1.55 mmol) was added to a stirring solution of the product ofExample 65A (122 mg, 0.31 mmol) in tetrahydrofuran (5.0 mL) at roomtemperature under nitrogen. The turbid solution was stirred at roomtemperature for 4 hours. The reaction was quenched by addition ofmethanol (1 mL), followed after 5 minutes by water (5 mL) and 25% NaOH(0.5 mL). The aqueous layer was separated and extracted with ethylacetate (2×5 mL) and the combined organic phase was washed with brine (5mL), dried (Na₂SO₄) and concentrated under vacuum to provide a residuethat was purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm100 Å AXIA column (30×75 mm), eluted with methanol:10 mM (NH₄)₂CO₃ inwater (50:50-95:5) to provide the title compound ¹H NMR (300 MHz, CDCl₃)δ ppm 1.62-1.94 (m, 6H), 1.97-2.12 (m, 2H), 2.13-2.26 (m, 1H), 2.30-2.49(m, 1H), 2.51-2.69 (m, 2H), 2.72-2.87 (m, 1H), 2.91-3.03 (m, 1H),3.02-3.15 (m, 2H), 3.17-3.70 (m, 6H), 6.74 (dd, J=7.8, 4.7 Hz, 1H), 6.92(dd, J=7.8, 1.4 Hz, 1H), 7.01 (t, J=8.6 Hz, 2H), 7.27-7.39 (m, 2H), 7.79(dd, J=4.7, 1.7 Hz, 1H); MS (DCI) m/z 381 (M+H)⁺.

Example 66 tert-butyl6-(4-bromobenzyl)-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylateExample 66A tert-butyl1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepinc-3(4H)-carboxylate

The product of Example 1 (147.6 mg, 0.47 mmol) was dissolved in 1 M BH₃in tetrahydrofuran (3 mL, 3 mmol). The reaction was heated to 60° C. for3 hours. The reaction was concentrated, and then the residue wasdissolved in propylamine (3 mL) and stirred at ambient temperature for 2hours. The reaction mixture was concentrated again and purified by HPLCusing the method described in Example 4 to give the title compound: MS(DCI/NH₃) m/z 304 (M+H)⁺.

Example 66B tert-butyl6-(4-bromobenzyl)-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate

The product of Example 66A (82.5 mg, 0.27 mmol) and 4-bromobenzaldehyde(77.7 mg, 0.42 mmol) were processed according to the procedure forExample 17 and purified by preparative HPLC using the method describedin Example 4 to give the title compound: ¹H NMR (500 MHz, pyridine-d₅) δppm 1.55 (s, 9H), 2.61-2.63 (m, 1H), 2.72-2.30 (m, 1H), 3.09-3.13 (m,1H), 3.19-3.21 (m, 1H), 3.24-3.28 (m, 1H), 3.34-3.48 (m, 3H), 3.53-3.55(m, 2H), 3.71 (d, J=13.4 Hz, 1H), 4.01 (d, J=13.4 Hz, 1H), 6.95 (d,J=7.9 Hz, 1H), 7.02 (td, J=7.3, 0.9 Hz, 1H), 7.10 (dd, J=7.3, 1.2 Hz,1H), 7.31-7.34 (m, 3H), 7.54-7.56 (m, 2H); MS (DCI/NH₃) m/z 472 (M+H)⁺.

Example 67 tert-butyl6-(4-bromobenzyl)-5-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate

Sodium hydride (60 weight %, 27.9 mg, 0.70 mmol) was washed with heptane(2 mL) and then suspended in N,N-dimethylformamide (2 mL). The productof Example 1 (149.2 mg, 0.47 mmol) was added and the reaction stirred atambient temperature for 2 hours. 4-Bromobenzyl bromide (196.6 mg, 0.79mmol) was added and allowed to react for 16 hours. The reaction wasquenched with methanol and purify by preparative HPLC using the methoddescribed in Example 4 to give the title compound: ¹H NMR (500 MHz,pyridine-d₅) δ ppm 1.54 (s, 9H), 3.03-3.10 (m, 2H), 3.17-3.21 (m, 1H),3.47-3.56 (m, 1H), 3.93 (dd, J=9.8, 2.8 Hz, 1H), 4.08-4.11 (m, 1H),4.69-4.72 (m, 1H), 4.76 (d, J=14.9 Hz, 1H), 4.88 (d, J=14.3 Hz, 1H),6.94-7.02 (m 3H), 7.22-7.24 (m, 2H), 7.29-7.33 (m, 1H), 7.48-7.50 (m,2H); MS (DCI/NH₃) m/z 486 (M+H)⁺.

Example 685-[(2S)-azetidin-2-ylmethyl]-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepineExample 68A tert-butyl(2S)-2-{[9-(4-fluorobenzyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl]carbonyl}azetidine-1-carboxylate

O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (177 mg, 0.465 mmol) was added to a mixture of theproduct of Example 64C (97 mg, 0.31 mmol) and(S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (94 mg, 0.465mmol, prepared as described in J. Med. Chem. 2005, 48, 7637-7647) inCH₂Cl₂ (2.0 mL). Diisopropylethylamine (0.108 mL, 0.620 mmol) was added,and the mixture was stirred at room temperature for 18 hours. Themixture was applied directly to a column of silica gel and eluted with5% methanol-CH₂Cl₂ to provide the title compound: MS (DCI) m/z 496(M+H)⁺.

Example 68B tert-butyl(2S)-2-{[9-(4-fluorobenzyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl]methyl}azetidine-1-carboxylate

A solution of alane-dimethylethylamine complex (0.5 M in toluene, 3.1mL, 1.55 mmol) was added to a solution of the product of example 68A(154 mg, 0.31 mmol) in tetrahydrofuran (5.0 mL) at room temperatureunder nitrogen. The turbid solution was stirred at room temperature for3 hours and then quenched by addition of methanol (1 mL), followed after5 minutes by water (5 mL) and 25% NaOH (0.5 mL). The aqueous layer wasseparated and extracted with ethyl acetate (2×5 mL), and the combinedorganic phases were washed with brine (5 mL), dried (Na₂SO₄) andconcentrated under vacuum to provide residue which was purified bypreparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column(30×75 mm) eluted with methanol:110 mM (NH₄)₂CO₃ in water (50:50-95:5)to provide the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.45 (s,9H), 1.70-1.92 (m, 2H), 1.91-2.08 (m, 1H), 2.11-2.27 (m, 2H), 2.32-2.44(m, 1H), 2.52-2.62 (m, 1H), 2.68-2.83 (m, 1H), 3.03-3.18 (m, 1H),3.23-3.70 (m, 8H), 3.71-3.89 (m, 2H), 4.27-4.45 (m, 1H), 6.69-6.77 (m,1H), 6.97-7.04 (m, 2H), 7.04-7.10 (m, 1H), 7.31 (dd, J=8.3, 5.6 Hz, 2H),7.81 (dd, J=4.7, 1.4 Hz, 1H); MS (DCI) m/z 482 (M+H)⁺.

Example 68C5-[(2S)-azetidin-2-ylmethyl]-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine

Trifluoroacetic acid (1 mL, 13 mmol) was added to an ice-cooled solutionof the product of Example 68B (51 mg, 0.106 mmol) in CH₂Cl₂ (2 mL). Thesolution was stirred with ice cooling for 30 minutes and then allowed towarm to room temperature. After 1 hour, the reaction solution wasconcentrated under vacuum to a residue that was purified by HPLC (30×100mm, C18, Waters XBridge™ column eluted with 0.1 M aqueous(NH₄)₂CO₃-methanol, 80:20-0:100 over 15 minutes) to provide the titlecompound: ¹H NMR (300 MHz, CD₃OD) δ ppm 1.64-1.90 (m, 2H), 1.98-2.14 (m,1H), 2.15-2.27 (m, 1H), 2.27-2.42 (m, 2H), 2.67 (d, J=10.7 Hz, 1H),2.76-2.86 (m, 1H), 2.92-3.11 (m, 1H), 3.19-3.45 (m, 6H), 3.46-3.66 (m,4H), 4.05-4.22 (m, 1H), 6.77-6.91 (m, 1H), 7.05 (t, J=8.7 Hz, 2H), 7.15(d, J=7.9 Hz, 1H), 7.37 (dd, J=8.3, 5.6 Hz, 2H), 7.68-7.76 (m, 1H); MS(DCI) m/z 382 (M+H)⁺.

Example 695-(azetidin-3-ylmethyl)-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepineExample 69A tert-butyl3-{[9-(4-fluorobenzyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl]carbonyl}azetidine-1-carboxylate

O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (177 mg, 0.465 mmol) was added to a mixture of theproduct of Example 64C (97 mg, 0.31 mmol) and1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (94 mg, 0.465 mmol)in CH₂Cl₂ (2 mL). Diisopropylethylamine (0.108 mL, 0.620 mmol) wasadded, and the mixture was stirred at room temperature for 18 hours. Thereaction mixture was applied directly to a column of silica gel andeluted with 5% methanol-CH₂Cl₂ to provide the title compound: MS (DCI)m/z 496 (M+H)⁺.

Example 69B tert-butyl3-{[9-(4-fluorobenzyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl]methyl}azetidine-1-carboxylate

Alane-dimethylethylamine complex (0.5 Min toluene, 3.1 mL, 1.55 mmol)was added to a solution of the product of Example 69A (154 mg, 0.31mmol) in tetrahydrofuran (5.0 mL) at room temperature under nitrogen.The cloudy solution was stirred at room temperature for 2.5 hours andthen quenched by addition of methanol (1 mL), followed after minutes bywater (5 mL) and 25% NaOH (0.5 mL). The aqueous layer was separated andextracted with ethyl acetate (2×6 mL). The combined organic phases werewashed with brine (5 mL), dried (Na₂SO₄) and concentrated under vacuumto provide a residue that was further purified by preparative HPLC on aPhenomenex® Luna® C8(2) 5 μm 100 Å AXIA column (30×75 mm) eluted withmethanol:10 mM (NH₄)₂CO₃ in water (50:50-95:5) to provide the titlecompound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.43 (s, 9H), 1.62-1.87 (m, 2H),2.12 (t, J=10.0 Hz, 1H), 2.34 (td, J=10.7, 2.7 Hz, 1H), 2.59 (d, J=10.9Hz, 1H), 2.72-2.86 (m, 2H), 2.89-3.00 (m, 1H), 3.14-3.26 (m, 1H), 3.28(d, J=7.5 Hz, 2H), 3.31-3.43 (m, 2H), 3.44-3.56 (m, 2H), 3.56-3.63 (m,2H), 3.69 (dt, J=12.8, 3.1 Hz, 1H), 3.96 (td, J=8.5, 3.7 Hz, 2H), 6.75(dd, J=7.8, 4.7 Hz, 1H), 6.96 (dd, J=7.8, 1.4 Hz, 1H), 6.98-7.06 (m,2H), 7.31 (dd, J=8.5, 5.4 Hz, 2H), 7.86 (dd, J=4.7, 1.7 Hz, 1H); MS(DCI) m/z 482 (M+H)⁺.

Example 69C5-(azetidin-3-ylmethyl)-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine

Trifluoroacetic acid (1 mL, 12.98 mmol) was added to an ice-cooledsolution of the product of Example 69B (75 mg, 0.156 mmol) in CH₂Cl₂ (2mL). The solution was stirred with ice cooling for 30 minutes and thenallowed to warm to room temperature and concentrated to dryness. Thecrude material was taken in 20% K₂CO₃(aq) (20 mL) and 25% NaOH (1 mL)and extracted with CH₂Cl₂ (2×20 mL). The organic extract was dried(Na₂SO₄) and concentrated to a residue that was purified by HPLC (30×100mm, C18, Waters XBridge™ column eluted with 0.1 M aqueous(NH₄)₂CO₃-methanol, 80:20-0:100 over 15 minutes) to provide the titlecompound: ¹H NMR (300 MHz, CD₃OD) δ ppm 1.64-1.90 (m, 2H), 2.18 (t,J=10.3 Hz, 1H), 2.32 (dt, J=10.8, 3.1 Hz, 1H), 2.67 (d, J=10.5 Hz, 1H),2.81 (d, J=10.8 Hz, 1H), 2.90-3.12 (m, 2H), 3.18-3.44 (m, 7H), 3.47-3.60(m, 3H), 3.67 (td, J=8.4, 2.9 Hz, 2H), 6.85 (dd, J=7.8, 5.1 Hz, 1H),7.00-7.10 (m, 2H), 7.12-7.18 (m, 1H), 7.31-7.42 (m, 2H), 7.72 (dd,J=4.9, 1.5 Hz, 1H); MS (DCI) m/z 382 (M+H)⁺.

Example 706-(4-bromobenzyl)-2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one

The product of Example 67 (109.4 mg, 0.23 mmol) was dissolved indichloromethane (3 mL), and treated with trifluoroacetic acid (0.5 mL,6.5 mmol) for 1 hour at ambient temperature. The reaction wasconcentrated and purify by preparative HPLC using the method describedin Example 4 to give the title compound: ¹H NMR (500 MHz, pyridine-ds) δppm 2.97-3.03 (m, 2H), 3.08-3.15 (m, 1H), 3.37 (dd, J=12.4, 8.4 Hz, 1H),3.58 (dd, J=12.4, 2.6 Hz, 1H), 3.98 (dd, J=8.4, 2.9 Hz, 1H), 4.20 (d,J=14.6 Hz, 1H), 4.72-7.85 (m, 3H), 3.91-6.95 (m, 1H), 6.98-6.99 (m, 1H),7.05 (d, J=7.6 Hz, 1H), 7.25-7.26 (m, 2H), 7.30-7.33 (m, 1H), 7.48-7.51(m, 2H); MS (DCI/NH₃) m/z 386 (M+H)⁺.

Example 716-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The product of Example 66 (79.5 mg, 0.17 mmol) was dissolved indichloromethane (3 mL), and treated with trifluoroacetic acid (0.5 mL,6.5 mmol) for 1 hour at ambient temperature. The reaction wasconcentrated and purify by preparative HPLC using the method describedin Example 9 to give the title compound as the tris-trifluoroacetic acidsalt: ¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.57-2.67 (m, 2H), 3.43-3.51(m, 3H), 3.58-3.61 (m, 1H), 3.66-3.76 (m, 6H), 4.24 (d, J=13.1 Hz, 1H),6.92 (d, J=7.9 Hz, 1H), 7.09 (td, J=7.3, 0.9 Hz, 1H), 7.18 (dd, J=7.3,1.5 Hz, 1H), 7.30-7.32 (m, 2H), 7.36 (td, J=7.6, 1.5 Hz, 1H), 7.53-7.56(m, 2H); MS (DCI/NH₃) m/z 372 (M+H)⁺. Elemental analysis calculated forC₁₉H₂₂BrN₃.3 TFA: C, 42.03; H, 3.53; N, 5.88; F, 23.94. Found: C, 42.10;H, 3.44; N, 5.82; F, 23.80.

Example 72cyclopropyl(7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl)methanoneExample 72A tert-butyl6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine-9(5H)-carboxylate

A solution of alane-N,N-dimethylethylamine complex (0.5 M in toluene,5.0 mL, 2.50 mmol) was added dropwise over 2 minutes to a solution ofthe product of Example 64A (506 mg, 1.59 mmol) in dry tetrahydrofuran(22 mL). The reaction was stirred at room temperature for 5 hours.Additional portions of alane-N,N-dimethylethylamine complex (0.5 M intoluene, 5.0 mL, 2.50 mmol) were added after 1 hour, and again after 4hours. Methanol (10 mL) was added, followed after 10 minutes by water(20 mL) and 25% NaOH (3 mL). The mixture was stirred for 10 minutes, andthe aqueous layer was separated and extracted with ethyl acetate (30mL). The combined organic phases were washed with brine, dried (Na₂SO₄)and concentrated under vacuum. The residue was purified bychromatography (SiO₂, eluted with ethyl acetate-ethanol, 90:10) toprovide the title compound: ¹H NMR (300 MHz, CDCl₃) δ ppm 1.48 (s, 9H),1.73-1.88 (m, 1H), 1.90-2.07 (m, 1H), 3.17-3.40 (m, 2H), 3.40-3.83 (m,7H), 6.67 (dd, J=7.8, 4.8 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 7.75 (dd,J=4.7, 1.7 Hz, 1H); MS (DCI) m/z 305 (M+H)⁺.

Example 72B tert-butyl5-(cyclopropylcarbonyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine-9(5H)-carboxylate

A solution of cyclopropylcarbonyl chloride (0.072 mL, 0.79 mmol) CH₂Cl₂(1 mL) was added to an ice-cooled solution of the product of Example 72A(218 mg, 0.716 mmol) in CH₂Cl₂ (5 mL). The reaction was stirred with icecooling under nitrogen for 45 minutes and then it was allowed to warm toroom temperature for 4 hours. The reaction was quenched by addition ofmethanol (2 mL) and the solution was stirred for 10 minutes. Thereaction mixture was then concentrated under vacuum. The residue waspurified by HPLC (30×100 mm, C18, Waters XBridge™ column eluted with 0.1M aqueous (NH₄)₂CO₃-methanol, 80:20-0:100 over 15 minutes) to providethe title compound: MS (DCI) m/z 373 (M+H)⁺.

Example 72Ccyclopropyl(7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl)methanone

A solution of HCl (4 M in dioxane, 250 μl, 1 mmol) was added to asolution of the product of Example 72B (26.3 mg, 0.071 mmol) in CH₂Cl₂(1.3 mL), and the mixture was stirred at room temperature for 70 hours.The mixture was concentrated under vacuum, and the residue wascrystallized from ethyl acetate-ethanol (4 mL, 2:1) to provide the titlecompound as the bis-hydrochloride salt: ¹H NMR (400 MHz, pyridine-d₅,110° C.) δ ppm 0.41 (dd, J=7.8, 3.5 Hz, 2H), 0.85-0.97 (m, 2H),1.06-1.21 (m, 1H), 1.51-1.64 (m, 1H), 1.66-1.77 (m, 1H), 2.91 (t, J=11.0Hz, 1H), 3.25-3.45 (m, 3H), 3.53-4.09 (m, 5H), 6.77 (dd, J=7.6, 4.9 Hz,1H), 7.37 (dd, J=7.6, 1.5 Hz, 1H), 8.16 (dd, J=4.6, 1.5 Hz, 1H); MS(DCI) m/z 273 (M+H)⁺. Elemental analysis is calculated forC₁₅H₂₀N₄O.2HCl.0.5H₂O.0.4 EtOAc: C, 51.19; H, 6.78; N, 14.38. Found: C,51.23; H, 6.57; N, 14.12.

Example 736-(4-bromobenzyl)-3-(4-fluorobenzyl)-2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one

The product of Example 70 (84.2 mg, 0.22 mmol) and 4-fluorobenzaldehyde(48.7 mg, 0.39 mmol) were processed according to the procedure forExample 17 and purified by preparative HPLC using the method describedin Example 9 to give the title compound as the trifluoroacetic acidsalt: ¹H NMR (400 MHz, benzene-d₆) δ ppm 2.29 (td, J=11.1, 2.8 Hz, 1H),2.67 (t, J=10.5 Hz, 1H), 2.86-2.89 (m, 1H), 3.04 (dt, J=11.3, 2.6 Hz,1H), 3.19 (td, J=11.2, 2.6 Hz, 1H), 3.48-3.51 (m, 1H), 3.57-3.62 (m,2H), 3.96 (d, J=13.7 Hz, 1H), 4.04 (dd, J=10.4, 2.2 Hz, 1H), 4.72-7.85(m, 2H), 5.03 (d, J=14.0 Hz, 1H), 6.95-7.01 (m, 2H), 7.06 (d, J=7.9 Hz,1H), 7.10-7.14 (m, 2H), 7.25-7.29 (m, 2H), 7.30-7.35 (m, 1H), 7.39-7.43(m, 2H), 7.49-7.52 (m, 2H); MS (DCI/NH₃) m/z 494 (M+H)⁺. Elementalanalysis calculated for C₂₆H₂₅BrFN₃O.1.1 TFA: C, 54.65; H, 4.24; N,6.78. Found: C, 54.82; H, 4.01; N, 6.68.

Example 74[5-(cyclopropylmethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-9(5H)-yl](pyridin-3-yl)methanoneExample 74A5-(cyclopropylmethyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine

A solution alane-N,N-dimethylethylamine (0.5 M in toluene, 2.84 mL, 1.42mmol) was added under nitrogen to an ice-cooled solution of the productof Example 72B (176 mg, 0.473 mmol) in tetrahydrofuran (8 mL). Thereaction was stirred with ice cooling for 15 minutes and then warmed toroom temperature and stirred for 30 minutes. Methanol (1 mL) was addedfollowed after 5 minutes by addition of 25% NaOH (1 mL). The mixture wasstirred for 10 minutes and then concentrated under vacuum. The residuewas taken up with brine (10 mL) and extracted with CH₂Cl₂ (2×20 mL). Thecombined organic phases were dried (Na₂SO₄) and concentrated undervacuum. The residue was dissolved in CH₂Cl₂ (5 mL) and stirred with icecooling under nitrogen for 10 minutes. Trifluoroacetic acid (1.0 mL, 13mmol) was added gradually over 0.5 minute, and the reaction was stirredwith ice cooling for 1 hour and then warmed to room temperature for 1hour. The solution was concentrated under vacuum, and the residue waspurified by HPLC (30×100 mm, C18, Waters XBridge™ column eluted with 0.1M aqueous (NH₄)₂CO₃-methanol, 80:20-0:100 over 15 minutes) to providethe title compound: ¹H NMR (300 MHz, CD₃OD) δ ppm 0.18-0.27 (m, 2H),0.51-0.60 (m, 2H), 0.93-1.09 (m, 1H), 1.67-1.80 (m, 1H), 1.80-1.94 (m,1H), 2.73-2.86 (m, 2H), 2.87-3.04 (m, 4H), 3.11-3.28 (m, 3H), 3.41-3.51(m, 2H), 6.84 (dd, J=7.8, 5.1 Hz, 1H), 7.12 (dd, J=8.0, 1.5 Hz, 1H),7.70 (dd, J=5.1, 1.7 Hz, 1H); MS (DCI) m/z 259 (M+H)⁺.

Example 74B[5-(cyclopropylmethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-9(5H)-yl](pyridin-3-yl)methanone

Nicotinoyl chloride hydrochloride (58.2 mg, 0.317 mmol) was added atroom temperature to a solution of the product of Example 74A (82 mg,0.317 mmol) in CH₂Cl₂ (4 mL) and triethylamine (0.111 mL, 0.793 mmol).The mixture was stirred at room temperature for 30 minutes and thenconcentrated under vacuum. The residue was purified by HPLC (30×100 mm,C18, Waters XBridge™ column eluted with 0.1 Maqueous (NH₄)₂CO₃-methanol,40:60-0:100 over 15 minutes) to provide the title compound: ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.16-0.21 (m, 2H), 0.45-0.54 (m, 2H), 0.93-1.03 (m,1H), 1.61-1.75 (m, 1H), 1.79-1.91 (m, 1H), 2.90-3.05 (m, 2H), 3.19-3.30(m, 2H), 3.34-3.50 (m, 4H), 3.54-3.64 (m, 1H), 3.71-3.92 (m, 2H), 6.74(dd, J=7.8, 4.7 Hz, 1H), 7.00 (dd, J=7.9, 1.5 Hz, 1H), 7.45 (ddd, J=7.9,4.9, 0.9 Hz, 1H), 7.65 (dd, J=4.6, 1.5 Hz, 1H), 7.83 (ddd, J=8.1, 2.0,1.8 Hz, 1H), 8.58-8.67 (m, 2H); MS (ESI) m/z 364 (M+H)⁺.

Example 751,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl(morpholin-4-yl)methanone

To the product of Example 14 (1.05 g, 2.58 mmol) and ethanol (20 ml) wasadded 20% Pd(OH)₂/C, wet (0.210 g, 1.495 mmol) in a 50 mL pressurebottle. The reaction was stirred for 1 hour at 30 psi (H₂) and 50° C.The mixture was filtered through a nylon membrane and concentrated togive the title compound: ¹H NMR (400 MHz, pyridine-d₅) δ ppm 2.95-3.05(m, 5H), 3.12-3.14 (m, 2H), 3.18-3.24 (m, 3H), 3.34-3.40 (m, 2H),3.64-3.68 (m, 2H), 3.72-3.84 (m, 3H), 4.48 (d, J=12.8 Hz, 1H), 4.87 (d,J=12.8 Hz, 1H), 6.95 (dd, J=7.9, 0.9 Hz, 1H), 7.03 (td, J=7.4, 1.1 Hz,1H), 7.26 (dd, J=7.5, 1.4 Hz, 1H), 7.37 (dd, J=7.6, 1.5 Hz, 1H); (MS(DCI/NH₃) m/z 317 (M+H)⁺.

Example 76[3-(4-fluorobenzyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl](morpholin-4-yl)methanone

The product of Example 75 (82.2 mg, 0.26 mmol) and 4-fluorobenzaldehyde(49.9 mg, 0.40 mmol) were processed according to the procedure forExample 17 and purified by preparative HPLC using the method describedin Example 4 to give the title compound: ¹H NMR (500 MHz, pyridine-d₅) δppm 2.33 (td, J=10.1=2, 3.2 Hz, 1H), 2.43-2.47 (m, 1H), 2.73-2.77 (m,2H), 3.11-3.24 (m, 6H), 3.35-3.39 (m, 2H), 3.39-3.50 (m, 2H), 3.65-3.68(m, 2H), 3.73-3.76 (m, 2H), 3.85 (dd, J=14.5, 3.8 Hz, 1H), 4.50 (d,J=13.2 Hz, 1H), 4.86 (d, J=12.8 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 7.04(td, J=7.5, 0.9 Hz, 1H), 7.14-7.18 (m, 2H), 7.27 (dd, J=7.3, 1.2 Hz,1H), 7.36 (td, J=7.7, 1.4 Hz, 1H), 7.39-7.41 (m, 2H); MS (DCI/NH₃) m/z425 (M+H)⁺. Elemental analysis calculated for C₂₄H₂₉FN₄O₂.015H₂O: C,67.47; H, 6.91; N, 13.11. Found: C, 67.13; H, 6.52; N, 12.96.

Example 77(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(morpholin-4-yl)methanone

The product of Example 75 (120.6 mg, 0.38 mmol) was dissolved in formicacid (4 mL). A solution of formaldehyde (36 weight %, 1 mL) was added,and the reaction was heated to 100° C. for 1 hour. The reaction wasconcentrated and purified by preparative HPLC using the method describedin Example 4 to give the title compound: ¹H NMR (500 MHz, pyridine-d₅) δppm 2.22 (s, 3H), 2.24-2.36 (m, 2H), 2.65-2.68 (m, 2H), 3.09-3.21 (m,2H), 3.23-3.25 (m, 4H), 3.38-3.41 (m, 2H), 3.68-3.70 (m, 2H), 3.74-3.76(m, 2H), 3.83-3.88 (m, 1H), 4.50 (d, J=12.8 Hz, 1H), 4.84 (d, J=12.8 Hz,1H), 6.95-7.96 (m, 1H), 7.04 (td, J=7.4, 1.1 Hz, 1H), 7.26 (dd, J=7.3,1.5 Hz, 1H), 7.36 (td, J=7.6, 1.5 Hz, 1H); MS (DCI/NH₃) m/z 331 (M+H)⁺.

Example 782-[2-(3-benzyl-2,3,4,4a,5,6-hexahydropyrazino[1,2-a][1,5]benzodiazepin-7(1H)-yl)-2-oxoethyl]pyridazin-3(2H)-one

A solution of the product of Example 26 (167 mg, 0.569 mmol) and2-(6-oxopyridazin-1(6H)-yl)acetic acid (95 mg, 0.616 mmol, prepared asdescribed in King, J. A., et al. J. Am. Chem. Soc. 1952, 74, 3222-3224)in tetrahydrofuran (15 mL) and diisopropylethylamine (0.151 mL, 0.867mmol) was cooled in ice-water under nitrogen. SolidO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (302 mg, 0.794 mmol) was added all at once, and themixture was stirred with ice cooling for 1 hour and then allowed to warmto room temperature. After 65 hours, the reaction mixture wasconcentrated under vacuum, and the residue was purified by HPLC (30×100mm, C18, Waters XBridge™ column eluted with aqueous (NH₄)₂CO₃-methanol,80:20-0:100 over 15 minutes) to provide the title compound: ¹H NMR (400MHz, pyridine-d₅) δ ppm 1.24-1.90 (m, 2H), 2.20-2.92 (m, 5H), 2.98-3.19(m, 2H), 3.33-3.50 (m, 2H), 3.50-3.78 (m, 1H), 4.29-4.82 (m, 2H),5.03-5.22 (m, 1H), 6.87-7.19 (m, 4H), 7.26-7.48 (m, 7H), 7.71-7.80 (m,1H); MS (ESI) m/z 430 (M+H)⁺. Elemental analysis is calculated forC₂₅H₂₇N₅O₂ 0.1 EtOAc: C, 69.60; H, 6.39; N, 15.98. Found: C, 69.69; H,6.33; N, 16.02.

Example 79(3-benzoyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(morpholin-4-yl)methanone

The product of Example 75 (105.8 mg, 0.33 mmol) and benzoyl chloride(69.5 mg, 0.49 mmol) were processed according to the procedure forExample 4 to give the title compound: ¹H NMR (500 MHz, pyridine-d₅) δppm 3.02-3.37 (m, 10H), 3.49-3.53 (m, 1H), 3.64-3.88 (m, 6H), 4.48 (d,J=12.8 Hz, 1H), 4.84 (d, J=12.2 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H), 7.07(td, J=7.3, 0.9 Hz, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H),7.42-7.46 (m, 3H), 7.67-7.68 (m, 2H); MS (DCI/NH₃) m/z 421 (M+H)⁺.Elemental analysis calculated for C₂₄H₂₈N₄O₃.0.25H₂O: C, 67.82; H, 6.76;N, 13.18. Found: C, 67.66; H, 6.54; N, 13.31.

Example 80morpholin-4-yl[3-(pyrimidin-2-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl]methanone

The product of Example 75 (77.6 mg, 0.33 mmol) and 2-chloropyrimidine(77.6 mg, 0.68 mmol) were processed according to the procedure forExample 9. The reaction was purified by preparative HPLC using themethod described in Example 4 to give the title compound: ¹H NMR (500MHz, pyridine-d₅) δ ppm 3.06-3.08 (m, 1H), 3.17-3.26 (m, 4H), 3.27-3.38(m, 3H), 3.45-3.49 (m, 1H), 3.60-3.72 (m, 5H), 3.86 (dd, J=14.3, 4.6 Hz,1H), 4.52 (d, J=13.1 Hz, 1H), 4.57-4.63 (m, 2H), 4.82 (d, J=13.1 Hz,1H), 6.52 (t, J=4.7 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H), 7.06 (td, J=7.4,1.1 Hz, 1H), 7.28 (dd, J=7.5, 1.4 Hz, 1H), 7.36 (td, J=7.6, 1.5 Hz, 1H),8.44 (d, J=4.6 Hz, 2H); MS (DCI/NH₃) m/z 395 (M+H)⁺. Elemental analysiscalculated for C₂₁H₂₆N6O₂.0.3H₂O: C, 63.08; H, 6.70; N, 21.02. Found: C,63.12; H, 6.84; N, 20.94.

Example 81morpholin-4-yl[3-(phenylsulfonyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl]methanone

The product of Example 75 (104.5 mg, 0.33 mmol) was dissolved indichloromethane (3 mL). Triethylamine (0.1 mL, 0.72 mmol) andbenzenesulfonyl chloride (92.0 mg, 0.52 mmol) were added, and thereaction mixture was stirred at ambient temperature for 1 hour. Thereaction was concentrated and purified by preparative HPLC using themethod described in Example 4 to give the title compound: ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.78-2.82 (m, 1H), 2.85-2.89 (m, 1H), 3.38-3.09(m, 1H), 3.16-3.25 (m, 5H), 3.32-3.36 (m, 2H), 3.64-3.73 (m, 2H),3.73-3.77 (m, 3H), 3.82-3.84 (m, 1H), 3.94 (dd, J=14.7, 3.7 Hz, 1H),4.34 (d, J=12.8 Hz, 1H), 4.63 (d, J=12.8 Hz, 1H), 6.90 (d, J=7.9 Hz,1H), 7.04 (td, J=7.3, 0.9 Hz, 1H), 7.21-7.22 (m, 1H), 7.32 (td, J=7.6,1.5 Hz, 1H), 7.53-7.58 (m, 3H), 7.97-7.99 (m, 2H); MS (DCI/NH₃) m/z 457(M+H)⁺.

Example 82[3-(4-chlorophenyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl](morpholin-4-yl)methanone

The product of Example 75 (101.4 mg, 0.32 mmol) was dissolved in toluene(3 mL). 4-Bromochlorobenzene (93.8 mg, 0.49 mmol),tris(dibenzylideneacetone)-dipalladium (15.1 mg, 0.016 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (34.0 mg, 0.055 mmol) andsodium tert-butoxide (95.0 mg, 0.99 mmol) were added. The reactionmixture was heated to 90° C. for 23 hours under nitrogen. The reactiontreated with water (35 mL) and extract with ethyl acetate (3×35 mL). Thecombined organic extracts were washed with brine (25 mL), dried overMgSO₄, filtered and concentrated. The residue was purified bypreparative HPLC using the method described in Example 4 to give thetitle compound: ¹H NMR (400 MHz, pyridine-d₅) δ ppm 2.97-3.03 (m, 1H),3.10-3.16 (m, 2H), 3.22-3.34 (m, 5H), 3.38-3.44 (m, 2H), 3.54-3.57 (m,1H), 3.60-3.62 (m, 1H), 3.66-3.71 (m, 2H), 3.73-3.78 (m, 2H), 3.93 (dd,J=14.3, 3.4 Hz, 1H), 4.53 (d, J=12.8 Hz, 1H), 4.83 (d, J=12.5 Hz, 1H),6.93-6.99 (m, 3H), 7.07 (td, J=7.3, 0.9 Hz, 1H), 7.29 (dd, J=7.5, 1.4Hz, 1H), 7.35-7.41 (m, 3H); MS (DCI/NH₃) m/z 427 (M+H)⁺. Elementalanalysis calculated for C₂₃H₂₇ClN₄O₂: C, 64.70; H, 6.37; N, 13.12.Found: C, 64.57; H, 6.29; N, 13.24.

Example 831-[6-(morpholin-4-ylcarbonyl)-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-3(4H)-yl]ethanone

The product of Example 75 (193.9 mg, 0.61 mmol) and acetic anhydride(188.7 mg, 1.85 mmol) were processed according to the procedure forExample 4 to give the title compound: ¹H NMR (500 MHz, pyridine-d₅) δppm (2:1 mixture of rotomers) 2.12 (s, 1H), 2.15 (s, 2H), 2.93-3.43 (m,10H), 3.61-3.86 (m, 6H), 4.37-4.55 (m, 2H), 4.76-4.81 (m, 1H), 6.92-6.95(m, 1H), 7.05-7.08 (m, 1H), 7.28-7.29 (m, 1H), 7.34-7.38 (m, 1H) ppm; MS(DCI/NH₃) m/z 359 (M+H)⁺. Elemental analysis calculated forC₁₉H₂₆N₄O₃.0.5H₂O: C, 62.11; H, 7.41; N, 15.25. Found: C, 62.11; H,7.39; N, 15.21.

Example 841-{4-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)carbonyl]piperidin-1-yl}ethanone

To a solution of3-benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine(44 mg, 0.15 mmol, Example 2) in dimethylacetamide (1.0 mL) was added1-acetylpiperidine-4-carboxylic acid (31 mg, 0.18 mmol) dissolved in asolution of dimethylacetamide (0.6 mL), followed by triethylamine (21μL, 0.20 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (57 mg, 0.15 mmol). The reaction mixture was shakenat 60° C. overnight. The reaction was filtered, checked by LC/MS andconcentrated to dryness. Purification of the residue via HPLC affordedthe title compound as the trifluoroacetic acid salt. ¹H NMR (500 MHz,pyridine-ds) δ ppm 1.72-1.93 (m, 3H), 2.05 (s, 3H), 2.30-2.47 (m, 2H),2.81-3.09 (m, 8H), 3.18-3.37 (m, 2H), 3.53-3.85 (m, 3H), 4.64 (d,J=23.50 Hz, 2H), 4.72-4.89 (m, 1H), 6.94-7.11 (m, 2H), 7.19-7.40 (m,6H), 7.41-7.50 (m, 2H); MS (ESI+) m/z 447 (M+H)⁺.

Example 85(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1H-pyrazol-4-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting1H-pyrazole-4-carboxylic acid for 1-acetylpiperidine-4-carboxylic acid.¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.26-2.66 (m, 2H), 2.88 (d, J=10.68Hz, 2H), 3.01-3.17 (m, 2H), 3.20-3.39 (m, 4H), 3.52-3.72 (m, 3H), 4.80(d, J=13.12 Hz, 1H), 5.05 (d, J=13.12 Hz, 1H), 6.91-7.12 (m, 4H),7.22-7.49 (m, 6H); MS (ESI+) m/z 388 (M+H)⁺.

Example 86(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1H-pyrazol-5-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting1H-pyrazole-5-carboxylic acid for 1-acetylpiperidine-4-carboxylic acid.¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.25 (dd, 2H), 2.49 (dd, 2H), 2.81(dd, J=10.83, 1.37 Hz, 2H), 3.12 (s, 4H), 3.27-3.61 (m, 3H), 6.87-7.13(m, 3H), 7.20-7.35 (m, 2H), 7.27-7.48 (m, 6H), 7.79 (d, J=1.83 Hz, 1H);MS (ESI+) m/z 388 (M+H)⁺.

Example 871-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-(morpholin-4-yl)ethanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting2-morpholinoacetic acid for 1-acetylpiperidine-4-carboxylic acid. ¹H NMR(500 MHz, pyridine-d₅) δ ppm 2.31-2.55 (m, 4H), 2.70 (s, 4H), 2.83-3.15(m, 3H), 3.19-3.41 (m, 6H), 3.69 (d, J=49.44 Hz, 6H), 4.75 (d, 2H), 6.99(d, J=7.93 Hz, 2H), 7.22-7.52 (m, 6H),); MS (ESI+) m/z 421 (M+H)⁺.

Example 88(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1,3-thiazol-4-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substitutingthiazole-4-carboxylic acid for 1-acetylpiperidine-4-carboxylic acid. ¹HNMR (500 MHz, pyridine-d₅) δ ppm 2.40 (s, 2H), 2.91 (d, J=10.99 Hz, 2H),3.14 (s, 2H), 3.25 (dd, J=10.99, 2.14 Hz, 2H), 3.59 (d, 4H), 4.57 (d,J=14.34 Hz, 1H), 4.77-5.01 (m, 2H), 6.90-7.12 (m, 2H), 7.22-7.46 (m,7H); MS (ESI+) m/z 405 (M+H)⁺.

Example 89(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1,3-thiazol-5-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substitutingthiazole-5-carboxylic acid for 1-acetylpiperidine-4-carboxylic acid. ¹HNMR (500 MHz, pyridine-d₅) δ ppm 2.28-2.63 (m, 2H), 2.85 (d, J=10.99 Hz,2H), 2.92-3.18 (m, 3H), 3.18-3.37 (m, 2H), 3.50 (s, 1H), 3.56 (s, 2H),4.76 (d, J=13.73 Hz, 1H), 4.98 (d, J=13.43 Hz, 1H), 6.91-7.13 (m, 2H),7.22-7.50 (m, 7H); MS (ESI+) m/z 405 (M+H)⁺.

Example 90(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1,2-oxazol-5-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substitutingisooxazole-5-carboxylic acid for 1-acetylpiperidine-4-carboxylic acid.¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.33 (d, 1H), 2.83 (d, 2H),2.89-3.39 (m, 6H), 3.56 (dd, 4H), 4.57-5.03 (m, 1H), 6.81-7.10 (m, 2H),7.22-7.52 (m, 7H); MS (ESI+) m/z 389 (M+H)⁺.

Example 911-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-3-(pyrrolidin-1-yl)propan-1-one

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting3-(pyrrolidin-1-yl)propanoic acid for 1-acetylpiperidine-4-carboxylicacid. ¹H NMR (500 MHz, pyridine-d₅) δ ppm 1.80-2.12 (m, 4H), 2.27-2.47(m, 2H), 2.71-3.12 (m, 5H), 3.22 (d, J=23.80 Hz, 2H), 3.40 (d, J=4.88Hz, 4H), 3.52 (d, J=14.34 Hz, 2H), 3.59-3.78 (m, 4H), 4.59 (d, J=13.12Hz, 1H), 4.63-4.86 (m, 1H), 6.90-7.08 (m, 2H), 7.27 (t, J=6.41 Hz, 3H),7.29-7.41 (m, 2H), 7.43 (d, J=7.32 Hz, 2H); MS (ESI+) m/z 419 (M+H)⁺.

Example 921-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-cyclopropylethanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting2-cyclopropylacetic acid for 1-acetylpiperidine-4-carboxylic acid. ¹HNMR (500 MHz, pyridine-d₅) δ ppm 0.24 (s, 2H), 0.54 (d, J=7.63 Hz, 2H),1.04-1.45 (m, 1H), 2.51 (s, 4H), 2.75-3.36 (m, 6H), 3.60 (s, 3H), 4.64(d, 2H), 6.98 (d, J=7.63 Hz, 2H), 7.27 (d, J=7.02 Hz, 2H), 7.27-7.38 (m,2H), 7.44 (d, J=7.32 Hz, 2H); MS (ESI+) m/z 376(M+H)⁺.

Example 93(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1H-pyrrol-2-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting1H-pyrrole-2-carboxylic acid for 1-acetylpiperidine-4-carboxylic acid.¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.21-2.43 (m, 1H), 2.38-2.60 (m,2H), 2.82 (dd, J=17.55, 10.83 Hz, 2H), 3.00-3.16 (m, 2H), 3.20 (dd,J=10.38, 3.05 Hz, 2H), 3.33-3.48 (m, 1H), 3.46-3.60 (m, 2H), 4.54 (dd,J=14.65, 3.36 Hz, 1H), 4.85 (d, J=13.12 Hz, 1H), 5.11 (d, J=13.12 Hz,1H), 6.29-6.52 (m, 1H), 6.80 (d, J=3.05 Hz, 1H), 6.91-7.08 (m, 2H),7.22-7.36 (m, 4H), 7.33-7.48 (m, 2H); MS (ESI+) m/z 387(M+H)⁺.

Example 94(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(3-furyl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substitutingfuran-3-carboxylic acid for 1-acetylpiperidine-4-carboxylic acid. ¹H NMR(500 MHz, pyridine-d₅) δ ppm 2.29-2.66 (m, 2H), 2.86 (d, J=10.99 Hz,4H), 2.98-3.18 (m, 2H), 3.15-3.37 (m, 2H), 3.53 (d, J=26.55 Hz, 3H),4.72 (d, J=13.43 Hz, 1H), 4.94 (d, J=13.43 Hz, 1H), 6.81 (s, 1H),6.92-7.14 (m, 2H), 7.27 (d, J=7.32 Hz, 2H), 7.33 (t, J=7.63 Hz, 2H),7.37-7.50 (m, 2H); MS (ESI+) m/z 388(M+H)⁺.

Example 95(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1,2,5-trimethyl-1H-pyrrol-3-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting1,2,5-trimethyl-1H pyrrole-3-carboxylic acid for1-acetylpiperidine-4-carboxylic acid. ¹H NMR (500 MHz, pyridine-d₅) δppm 2.07 (s, 3H), 2.30 (s, 3H), 2.34-2.55 (m, 2H), 2.71 (d, J=10.38 Hz,1H), 2.80-2.92 (m, 1H), 3.01 (d, J=6.10 Hz, 1H), 3.01 (d, J=6.10 Hz,1H), 3.20-3.39 (m, 6H), 3.50 (s, 1H), 3.52-3.68 (m, 2H), 4.76 (d,J=13.43 Hz, 1H), 4.98 (d, J=13.43 Hz, 1H), 5.99 (s, 1H), 6.88-7.08 (m,2H), 7.21-7.29 (m, 2H), 7.29-7.36 (m, 2H), 7.37-7.48 (m, 2H); MS (ESI+)m/z 429 (M+H)⁺.

Example 96(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(2,5-dimethyl-1H-pyrrol-3-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting1,2,5-dimethyl-1H pyrrole-3-carboxylic acid for1-acetylpiperidine-4-carboxylic acid. ¹H NMR (500 MHz, pyridine-d₅) δppm 2.22 (s, 3H), 2.32-2.58 (m, 6H), 2.75 (d, J=10.38 Hz, 1H), 3.03 (d,J=6.71 Hz, 1H), 3.11-3.22 (m, 2H), 3.19-3.41 (m, 2H), 3.57 (s, 1H), 4.79(d, J=13.43 Hz, 1H), 5.03 (d, J=13.43 Hz, 1H), 6.03 (s, 1H), 6.88-7.06(m, 2H), 7.26 (d, J=7.63 Hz, 2H), 7.32 (q, J=7.32 Hz, 3H), 7.37-7.47 (m,2H); MS (ESI+) m/z 415 (M+H)⁺.

Example 971-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)carbonyl]cyclopropanecarboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting1-carbamoylcyclopropanecarboxylic acid for1-acetylpiperidine-4-carboxylic acid. ¹H NMR (500 MHz, pyridine-d₅) δppm 1.45 (s, 1H), 1.48-1.75 (m, 2H), 2.27-2.64 (m, 2H), 2.90 (dd,J=18.16, 11.14 Hz, 2H), 3.02-3.21 (m, 3H), 3.19-3.34 (m, 2H), 3.51-3.71(m, 4H), 4.15 (s, 1H), 4.71-5.01 (m, 2H), 6.86-7.11 (m, 2H), 7.20-7.27(m, 2H), 7.28-7.38 (m, 3H), 7.39-7.49 (m, 2H); MS (ESI+) m/z 405 (M+H)⁺.

Example 981-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-(pyridin-3-yl)ethanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting2-(pyridine-3-yl)acetic acid for 1-acetylpiperidine-4-carboxylic acid.¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.39 (s, 2H), 2.87 (s, 2H),2.99-3.17 (m, 2H), 3.24 (d, J=9.77 Hz, 2H), 3.50 (s, 1H), 3.54-3.98 (m,5H), 4.62 (s, 1H), 4.71-4.92 (m, 1H), 6.72-7.08 (m, 2H), 7.28 (s, 2H),7.34 (d, J=7.32 Hz, 3H), 7.42 (s, 2H), 7.75 (s, 1H), 8.56 (s, 1H), 8.77(s, 1H); MS (ESI+) m/z 413 (M+H)⁺.

Example 99N-[2-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-oxoethyl]-2-furamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting2-(furan-2-carboxamido) acetic acid for 1-acetylpiperidine-4-carboxylicacid. ¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.51 (s, 2H), 2.75-3.13 (m,4H), 3.24 (s, 2H), 3.41-3.57 (m, 2H), 3.43-3.60 (m, 2H), 3.55-3.72 (m,1H), 3.58-3.75 (m, 2H), 4.52 (s, 2H), 4.70-4.88 (m, 1H), 6.44 (dd,J=3.36, 1.83 Hz, 1H), 6.84-7.08 (m, 2H), 7.21-7.31 (m, 1H), 7.34 (t,J=7.02 Hz, 2H), 7.37-7.47 (m, 2H), 7.51 (s, 2H); MS (ESI+) m/z 445(M+H)⁺.

Example 1001-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-methylpropan-1-one

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substitutingisobutyric acid for 1-acetylpiperidine-4-carboxylic acid. ¹H NMR (500MHz, pyridine-d₅) δ ppm 1.22 (d, J=6.41 Hz, 6H), 2.20-2.57 (m, 3H),2.78-3.04 (m, 4H), 3.05-3.18 (m, 1H), 3.24 (dd, J=10.83, 2.90 Hz, 2H),3.60 (s, 3H), 4.67-4.89 (m, 1H), 6.90-7.07 (m, 1H), 7.28 (d, J=7.02 Hz,2H), 7.34 (q, J=6.82 Hz, 3H), 7.38-7.49 (m, 2H); MS (ESI+) m/z 363(M+H)⁺.

Example 101(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(3,5-dimethyl-1,2-oxazol-4-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting3,5-dimethylisoxazole-4-carboxylic acid for1-acetylpiperidine-4-carboxylic acid. ¹H NMR (500 MHz, pyridine-d₅) δppm 2.20-2.38 (m, 5H), 2.34-2.57 (m, 2H), 2.55-2.80 (m, 1H), 2.87 (d,J=10.99 Hz, 1H), 3.02 (d, 1H), 3.15 (d, J=11.60 Hz, 1H), 3.18-3.34 (m,2H), 3.50 (s, 2H), 3.59 (s, 2H), 4.64 (s, 1H), 4.80 (s, 1H), 6.84-7.12(m, 2H), 7.26 (t, J=7.17 Hz, 2H), 7.29-7.38 (m, 3H), 7.37-7.48 (m, 2H);MS (ESI+) m/z 417 (M+H)⁺.

Example 102(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(5-methylpyrazin-2-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting5-methylpyrazine-2-carboxylic acid for 1-acetylpiperidine-4-carboxylicacid. ¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.33-2.55 (m, 4H), 2.83-3.35(m, 4H), 3.64 (d, J=12.82 Hz, 2H), 4.05 (s, 1H), 4.82-5.09 (m, 2H),6.74-7.13 (m, 3H), 7.21-7.32 (m, 2H), 7.28-7.45 (m, 5H), 7.43 (s, 2H),8.28 (s, 1H), 9.03 (s, 1H); MS (ESI+) m/z 414 (M+H)⁺.

Example 1031-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-(4-methylpiperazin-1-yl)ethanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting2-(4-methylpiperazin-1-yl)acetic acid for1-acetylpiperidine-4-carboxylic acid. ¹H NMR (500 MHz, pyridine-d₅) δppm 2.27-2.61 (m, 2H), 2.66-2.83 (m, 3H), 2.83-3.43 (m, 15H), 3.49-3.85(m, 5H), 4.75 (s, 1H), 7.00 (dd, J=11.44, 7.78 Hz, 2H), 7.19-7.27 (m,2H), 7.25-7.38 (m, 3H), 7.39-7.51 (m, 2H); MS (ESI+) m/z 434 (M+H)⁺.

Example 104(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(2-furyl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substitutingfuran-2-carboxylic acid for 1-acetylpiperidine-4-carboxylic acid. ¹H NMR(500 MHz, pyridine-d₅) δ ppm 2.19-2.54 (m, 2H), 2.88 (d, J=10.99 Hz,2H), 3.02 (d, 2H), 3.13 (d, J=11.60 Hz, 2H), 3.16-3.33 (m, 2H), 4.81 (d,J=13.73 Hz, 1H), 5.02 (d, J=13.73 Hz, 1H), 5.18 (d, 3H), 6.50 (dd,J=3.36, 1.83 Hz, 1H), 6.88-7.07 (m, 2H), 7.21-7.30 (m, 2H), 7.28-7.36(m, 3H), 7.36-7.47 (m, 2H); MS (ESI+) m/z 388 (M+H)⁺.

Example 105(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1-methyl-1H-pyrrol-2-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting1-methyl-1H-pyrrole-2-carboxylic acid for1-acetylpiperidine-4-carboxylic acid. ¹H NMR (500 MHz, pyridine-d₅) δppm 2.30-2.53 (m, 1H), 2.70 (d, J=10.38 Hz, 1H), 2.85 (d, J=10.99 Hz,1H), 2.95-3.10 (m, 1H), 3.10-3.19 (m, 1H), 3.19-3.36 (m, 2H), 3.57 (s,2H), 3.77 (s, 3H), 4.30 (dd, J=14.65, 3.05 Hz, 1H), 4.75 (d, J=13.73 Hz,1H), 4.98 (d, J=13.73 Hz, 1H), 6.15 (t, J=3.20 Hz, 1H), 6.46 (d, J=3.05Hz, 1H), 6.77 (s, 1H), 6.86-7.07 (m, 2H), 7.16 (d, J=7.32 Hz, 1H), 7.27(d, J=7.63 Hz, 2H), 7.28-7.36 (m, 3H), 7.36-7.48 (m, 2H); MS (ESI+) m/z401 (M+H)⁺.

Example 1061-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)propan-1-one

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting propionicacid for 1-acetylpiperidine-4-carboxylic acid. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 1.20 (t, J=6.87 Hz, 3H), 2.46 (d, J=40.59 Hz, 4H),2.76-2.99 (m, 4H), 3.11 (d, J=10.99 Hz, 1H), 3.25 (t, J=10.53 Hz, 2H),3.52-3.75 (m, 3H), 4.35-4.55 (m, 1H), 4.74 (s, 1H), 6.78-7.13 (m, 2H),7.27 (d, J=7.02 Hz, 2H), 7.27-7.39 (m, 3H), 7.44 (d, J=7.32 Hz, 2H); MS(ESI+) m/z 350(M+H)⁺.

Example 107(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(pyridin-4-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substitutingisonicotinic acid for 1-acetylpiperidine-4-carboxylic acid. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.51 (s, 3H), 2.89 (d, J=10.99 Hz, 2H), 3.26 (s,4H), 3.50 (s, 2H), 3.64 (d, J=12.51 Hz, 2H), 4.83 (d, 1H), 6.99 (d,J=7.93 Hz, 2H), 7.18-7.32 (m, 3H), 7.29-7.49 (m, 6H); MS (ESI+) m/z 399(M+H)⁺.

Example 1081-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)butan-1-one

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting butyricacid for 1-acetylpiperidine-4-carboxylic acid. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 0.97 (d, 3H), 1.78 (d, J=6.41 Hz, 2H), 2.46 (t, 4H),2.90 (dd, J=10.07 Hz, 4H), 3.13 (t, 2H), 3.26 (t, 2H), 3.50-3.74 (m,3H), 4.48 (d, 1H), 4.75 (d, 1H), 6.98 (d, J=7.02 Hz, 2H), 7.28 (d,J=7.02 Hz, 2H), 7.33 (s, 3H); MS (ESI+) m/z 364 (M+H)⁺.

Example 109(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(tetrahydrofuran-3-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substitutingtetrahydrofuran-3-carboxylic acid for 1-acetylpiperidine-4-carboxylicacid. ¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.09 (t, 1H), 2.39 (t, 3H),2.88 (d, J=10.99 Hz, 3H), 3.08 (dd, 4H), 3.25 (t, J=10.83 Hz, 2H),3.70-3.87 (m, 1H), 3.91-4.01 (m, 2H), 4.04-4.25 (m, 2H), 4.78 (s, 2H),6.99 (d, J=7.93 Hz, 2H), 7.20-7.31 (m, 2H), 7.34 (t, J=6.71 Hz, 3H),7.43 (d, J=7.02 Hz, 2H); MS (ESI+) m/z 392 (M+H)⁺.

Example 110(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(pyridin-3-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting nicotinicacid for 1-acetylpiperidine-4-carboxylic acid. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 2.51 (s, 3H), 2.88 (d, J=10.68 Hz, 2H), 3.11 (dd,1H), 3.27 (dd, 2H), 3.47 (t, 1H), 3.60 (t, 2H), 6.88-7.09 (m, 3H),7.19-7.49 (m, 8H), 7.83 (dd, J=7.93 Hz, 1H), 8.69 (t, J=4.58 Hz, 1H),8.88 (d, 1H); MS (ESI+) m/z 399 (M+H)⁺.

Example 1111-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-3-(piperidin-1-yl)propan-1-one

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting3-(piperidin-1-yl) propanoic acid for 1-acetylpiperidine-4-carboxylicacid. ¹H NMR (500 MHz, pyridine-d₅) δ ppm 1.45 (q, 2H), 1.79 (s, 3H),2.23-2.66 (m, 3H), 2.72-3.37 (m, 12H), 3.43-3.63 (m, 4H), 3.68 (d,J=13.12 Hz, 2H), 4.80 (dd, 2H), 6.80-7.09 (m, 2H), 7.24-7.31 (m, 2H),7.28-7.41 (m, 3H), 7.38-7.50 (m, 2H); MS (ESI+) m/z 433 (M+H).

Example 112(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(cyclopropyl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substitutingcyclopropanecarboxylic acid for 1-acetylpiperidine-4-carboxylic acid. ¹HNMR (500 MHz, pyridine-d₅) δ ppm 0.73 (d, J=3.66 Hz, 2H), 1.08 (d,J=7.02 Hz, 2H), 1.30-2.05 (m, 1H), 2.17-2.52 (m, 3H), 2.90 (t, J=12.05Hz, 2H), 3.11 (t, J=11.29 Hz, 1H), 3.15-3.38 (m, 2H), 3.61 (s, 2H),4.59-4.79 (m, 1H), 4.87 (s, 1H), 6.77-7.12 (m, 2H), 7.19-7.29 (m, 2H),7.23-7.38 (m, 3H), 7.36-7.50 (m, 2H); MS (ESI+) m/z 362 (M+H)⁺.

Example 1131-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-ethoxyethanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting2-ethoxyacetic acid for 1-acetylpiperidine-4-carboxylic acid. ¹H NMR(500 MHz, pyridine-d₅) δ ppm 0.86-1.36 (m, 2H), 2.28-2.41 (m, 2H), 2.88(dd, J=20.90, 10.83 Hz, 2H), 2.97-3.07 (m, 1H), 3.05-3.16 (m, 2H),3.15-3.36 (m, 2H), 3.54-3.86 (m, 5H), 4.57 (s, 1H), 4.65-4.91 (m, 2H),6.87-7.10 (m, 2H), 7.23-7.31 (m, 2H), 7.34 (q, J=6.71 Hz, 3H), 7.43 (d,J=7.02 Hz, 2H); MS (EST+) m/z 380 (M+H)⁺.

Example 114(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1-methylcyclopropyl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting1-methylcyclopropanecarboxylic acid for 1-acetylpiperidine-4-carboxylicacid. ¹H NMR (500 MHz, pyridine-d₅) δ ppm 0.32-0.76 (m, 2H), 0.85-1.03(m, 1H), 1.05-1.17 (m, 1H), 1.31 (s, 3H), 2.07-2.49 (m, 2H), 2.89 (d,J=10.99 Hz, 2H), 3.01-3.38 (m, 4H), 3.50 (s, 1H), 3.62 (d, J=1.22 Hz,2H), 4.13 (dd, J=14.34, 2.75 Hz, 1H), 4.81 (s, 2H), 6.86-7.10 (m, 2H),7.21-7.31 (m, 2H), 7.27-7.37 (m, 3H), 7.40-7.49 (m, 2H); MS (ESI+) m/z376 (M+H)⁺.

Example 115(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(cyclobutyl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substitutingcyclobutanecarboxylic acid for 1-acetylpiperidine-4-carboxylic acid. ¹HNMR (500 MHz, pyridine-d₅) δ ppm 1.86 (s, 2H), 2.12 (d, 2H), 2.22-2.60(m, 4H), 2.88 (d, J=11.29 Hz, 4H), 3.04-3.34 (m, 3H), 3.52-3.81 (m, 2H),4.39-4.68 (m, 1H), 4.77 (s, 1H), 6.97 (d, J=8.24 Hz, 2H), 7.18-7.27 (m,2H), 7.22-7.38 (m, 3H), 7.44 (d, J=6.10 Hz, 2H); MS (ESI+) m/z376(M+H)⁺.

Example 116(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(2-methylcyclopropyl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting2-methylcyclopranecarboxylic acid for 1-acetylpiperidine-4-carboxylicacid. ¹H NMR (500 MHz, pyridine-d₅) δ ppm 0.60 (s, 1H), 1.04 (d, J=5.80Hz, 2H), 1.11-1.64 (m, 4H), 2.15-2.50 (m, 2H), 2.91 (d, J=11.90 Hz, 4H),3.11 (d, J=11.29 Hz, 1H), 3.19-3.39 (m, 2H), 3.59 (d, J=13.12 Hz, 2H),4.68 (d, J=13.12 Hz, 1H), 4.82 (s, 1H), 6.71-7.13 (m, 2H), 7.24 (d,J=19.23 Hz, 2H), 7.27-7.41 (m, 3H), 7.43 (s, 2H); MS (ESI+) m/z 376(M+H)⁺.

Example 1171-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-3,3,3-trifluoropropan-1-one

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substituting3,3,3-trifluoropropanoicacid for 1-acetylpiperidine-4-carboxylic acid.¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.22-2.47 (m, 2H), 2.78-3.15 (m,4H), 3.17-3.42 (m, 2H), 3.52-3.85 (m, 4H), 4.57 (d, J=12.51 Hz, 1H),4.66-4.94 (m, 1H), 6.73-7.10 (m, 2H), 7.21-7.32 (m, 2H), 7.34 (d, J=6.71Hz, 3H), 7.41 (d, J=6.41 Hz, 2H); MS (ESI+) m/z 403 (M+H)⁺.

Example 118(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(tetrahydrofuran-2-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 84 substitutingtetrahydrofuran-2-carboxylic acid for 1-acetylpiperidine-4-carboxylicacid. ¹H NMR (500 MHz, pyridine-d₅) δ ppm 1.79 (s, 1H), 1.96 (s, 2H),2.23-2.62 (m, 2H), 2.74-3.18 (m, 4H), 3.25 (t, J=9.92 Hz, 1H), 3.51-3.69(m, 2H), 3.62 (t, 2H), 3.93 (d, J=58.59 Hz, 3H), 4.53-5.05 (m, 3H),6.76-7.13 (m, 2H), 7.28 (d, J=6.71 Hz, 2H), 7.28-7.39 (m, 3H), 7.43 (d,2H); MS (ESI+) m/z 392 (M+H)⁺.

Example 1193-benzyl-6-(4-methoxy-3-methylbenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

3-Benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine(43 mg, 0.15 mmol) was dissolved in a 1:1 solution ofdichloromethane/methanol (1.2 mL) followed by the addition of4-methoxy-3-methylbenzaldehyde (26 mg, 0.18 mmol) dissolved in a 1:1solution of dichloromethane/methanol (0.6 mL) followed by the additionof acetic acid (40 μL, 0.73 mmol). The reaction mixture was shaken at50° C. for 2 hours. Then macroporous poly(styrene-co-divinylbenzene)cyanoborohydride resin (MP-CNBH₃) (196 mg, 0.45 mmol, 2.25 mmol/gloading) was added and the reaction mixture was shaken overnight at 50°C. The resin was removed via filtration, and the filtrate wasconcentrated to dryness. Purification via HPLC afforded the titlecompound as the trifluoroacetic acid salt. ¹H NMR (500 MHz, pyridine-d₅)δ ppm 2.24 (s, 3H), 2.34-2.43 (m, 1H), 2.50 (s, 1H), 2.85-3.10 (m, 4H),3.27-3.36 (m, 2H), 3.59-3.79 (m, 6H), 4.06-4.21 (m, 2H), 4.35 (d,J=13.12 Hz, 1H), 4.53 (d, J=13.12 Hz, 1H), 6.82 (d, J=8.24 Hz, 1H), 6.96(d, J=7.93 Hz, 1H), 7.05 (t, J=7.17 Hz, 1H), 7.28-7.51 (m, 9H); MS(ESI+), m/z 428 (M+H)⁺.

Example 1203-benzyl-6-[(4,5-dimethyl-2-furyl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting4,5-dimethylfuran-2-carbaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹HNMR (500 MHz, pyridine-d₅) δ ppm 1.81 (s, 3H), 2.08 (s, 3H), 2.38-2.47(m, 1H), 2.57-2.65 (m, 1H), 2.83-3.02 (m, 4H), 3.23-3.39 (m, 2H),3.51-3.58 (m, 1H), 3.71 (s, 2H), 4.01 (d, J=4.88 Hz, 2H), 4.19 (d,J=13.12 Hz, 1H), 4.44 (d, J=12.82 Hz, 1H), 6.36 (s, 1H), 6.92 (d, J=7.63Hz, 1H), 7.01 (t, J=7.32 Hz, 1H), 7.26 (dd, J=7.32, 1.22 Hz, 1H),7.30-7.42 (m, 4H), 7.50 (d, J=7.32 Hz, 2H); MS (ESI+) m/z 402 (M+H)⁺.

Example 1213-benzyl-6-(4-ethoxybenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting4-ethoxybenzaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 1.27 (t, J=7.02 Hz, 3H), 2.34-2.44 (m, 1H),2.51-2.60 (m, 1H), 2.88-3.06 (m, 4H), 3.26-3.38 (m, 2H), 3.61-3.77 (m,3H), 3.90 (q, J=6.81 Hz, 2H), 4.11 (q, J=13.43 Hz, 2H), 4.30 (d, 1H),4.46 (d, 1H), 6.93-7.01 (m, 3H), 7.04 (t, J=7.32 Hz, 1H), 7.28-7.33 (m,2H), 7.39 (t, J=7.48 Hz, 3H), 7.50 (d, J=7.32 Hz, 2H), 7.58-7.61 (m,2H); MS (ESI+) m/z 428 (M+H)⁺.

Example 1223-benzyl-6-[(5-methyl-2-thienyl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting5-methylthiophene-2-carbaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹HNMR (500 MHz, pyridine-d₅) δ ppm 2.34 (s, 3H), 2.46-2.54 (m, 1H),2.62-2.75 (m, 2H), 2.84 (dd, J=13.58, 5.03 Hz, 1H), 2.99 (dd, J=20.29,10.83 Hz, 2H), 3.26-3.42 (m, 2H), 3.49-3.55 (m, 1H), 3.75-3.84 (m, 2H),3.91-4.06 (m, 3H), 4.31 (d, J=13.12 Hz, 1H), 6.67 (d, J=2.14 Hz, 1H),6.89-6.97 (m, 2H), 7.02 (t, J=7.32 Hz, 1H), 7.20 (s, 1H), 7.30-7.36 (m,2H), 7.40 (t, J=7.32 Hz, 2H), 7.54 (d, J=7.32 Hz, 2H); MS (ESI+) m/z 404(M+H)⁺.

Example 1233-benzyl-6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting4-bromobenzaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 2.48-2.57 (m, 1H) 2.62-2.81 (m, 3H), 3.00 (dd,J=21.21, 10.83 Hz, 2H), 3.29-3.44 (m, 2H), 3.53-3.59 (m, 1H), 3.67-3.84(m, 4H), 3.91 (d, J=13.12 Hz, 1H), 4.23 (d, J=13.12 Hz, 1H), 6.93 (d,J=7.93 Hz, 1H), 7.03 (t, J=7.32 Hz, 1H), 7.19 (dd, J=7.48, 1.37 Hz, 1H),7.30-7.43 (m, 6H), 7.51-7.57 (m, 4H); MS (ESI+) m/z 462 (M+H)⁺.

Example 1243-benzyl-6-(2-naphthylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting2-naphthaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 2.44-2.56 (m, 1H), 2.65 (t, J=9.92 Hz, 1H), 2.78-2.91(m, 2H), 2.98 (dd, J=15.71, 11.75 Hz, 2H), 3.28-3.45 (m, 2H), 3.61-3.67(m, 1H), 3.72-3.82 (m, 2H), 4.00-4.13 (m, 3H), 4.37 (d, J=12.82 Hz, 1H),6.95 (d, J=7.93 Hz, 1H), 7.04 (t, J=7.32 Hz, 1H), 7.25-7.42 (m, 5H),7.48-7.56 (m, 4H), 7.77 (dd, J=8.54, 1.53 Hz, 1H), 7.88-7.96 (m, 3H),8.01 (s, 1H); MS (ESI+) m/z 434 (M+H)⁺.

Example 1253-benzyl-6-(cyclopentylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substitutingcyclopentanecarbaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 1.15-1.58 (m, 6H), 1.84 (dd, J=12.66, 6.87 Hz,2H), 2.21-2.44 (m, 3H), 2.94-3.17 (m, 6H), 3.34 (d, J=6.71 Hz, 2H),3.57-3.69 (m, 2H), 3.82-3.91 (m, 1H), 4.51 (d, J=55.23 Hz, 2H), 6.98 (d,J=7.93 Hz, 1H), 7.03 (t, J=7.48 Hz, 1H), 7.32 (t, J=7.32 Hz, 1H),7.35-7.43 (m, 4H), 7.49 (d, J=7.32 Hz, 2H); MS (ESI+) m/z 376 (M+H)⁺.

Example 1263-benzyl-6-(quinolin-2-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substitutingquinoline-2-carbaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.49-2.60 (m, 1H), 2.72 (t, J=10.37 Hz, 1H),2.82-2.91 (m, 2H), 3.01 (d, J=10.07 Hz, 2H), 3.28-3.44 (m, 2H),3.52-3.59 (m, 1H), 3.81 (d, J=14.65 Hz, 2H), 4.06 (d, J=12.82 Hz, 1H),4.15-4.27 (m, 2H), 4.34 (d, J=12.82 Hz, 1H), 6.93 (d, J=7.63 Hz, 1H),7.01 (t, J=7.32 Hz, 1H), 7.26-7.29 (m, 1H), 7.33 (t, J=7.63 Hz, 2H),7.40 (t, J=7.48 Hz, 2H), 7.51-7.56 (m, 3H), 7.70-7.75 (m, 1H), 7.81 (d,J=8.54 Hz, 2H), 8.18 (d, J=8.54 Hz, 1H), 8.28 (d, J=8.54 Hz, 1H); MS(ESI+), m/z 434 (M+H)⁺.

Example 1273-benzyl-6-[(5-ethyl-2-furyl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting5-ethylfuran-2-carbaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR(500 MHz, pyridine-d₅) δ ppm 1.10 (t, J=7.48 Hz, 3H), 2.40-2.49 (m, 1H),2.49-2.57 (m, 2H), 2.64 (t, J=10.22 Hz, 1H), 2.84-3.02 (m, 4H),3.22-3.41 (m, 2H), 3.49-3.58 (m, 1H), 3.73 (s, 2H), 3.96-4.07 (m, 2H),4.14 (d, J=13.12 Hz, 1H), 4.41 (d, J=12.82 Hz, 1H), 6.03 (d, J=3.05 Hz,1H), 6.48 (d, J=3.05 Hz, 1H), 6.91 (d, J=7.93 Hz, 1H), 7.01 (t, J=7.32Hz, 1H), 7.28-7.43 (m, 5H), 7.51 (d, J=7.32 Hz, 2H); MS (ESI+) m/z 402(M+H)⁺.

Example 1284-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methyl]benzonitrile

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting4-formylbenzonitrile for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.57-2.71 (m, 3H), 2.77 (t, J=10.37 Hz, 1H),3.05 (d, J=10.98 Hz, 1H), 3.10 (d, J=10.98 Hz, 1H), 3.31-3.38 (m, 1H),3.41-3.48 (m, 1H), 3.51-3.57 (m, 1H), 3.63-3.79 (m, 3H), 3.90 (s, 2H),4.15 (d, J=13.12 Hz, 1H), 6.94 (d, J=7.93 Hz, 1H), 7.04 (t, J=7.02 Hz,1H), 7.16 (d, J=6.10 Hz, 1H), 7.30-7.37 (m, 2H), 7.40 (t, J=7.48 Hz,2H), 7.51 (d, J=8.24 Hz, 2H), 7.55-7.58 (m, 2H), 7.61-7.69 (m, 2H); MS(ESI+) m/z 409 (M+H)⁺.

Example 1293-benzyl-6-butyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substitutingbutyraldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 0.79 (t, J=7.32 Hz, 3H) 1.15-1.29 (m, 2H), 1.63-1.85(m, 2H), 2.24-2.33 (m, 1H), 2.39 (d, 1H), 2.80 (d, J=10.98 Hz, 1H),2.87-3.13 (m, 5H), 3.22-3.38 (m, 2H), 3.51-3.73 (m, 3H), 4.37 (s, 1H),4.54 (s, 1H), 6.98 (d, J=7.93 Hz, 1H), 7.04 (t, J=7.32 Hz, 1H),7.30-7.37 (m, 2H), 7.40 (t, J=7.63 Hz, 3H), 7.48 (d, J=7.02 Hz, 2H); MS(ESI+) m/z 350 (M+H)⁺.

Example 1303-benzyl-6-(4-chlorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting4-chlorobenzaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.52-2.59 (m, 1H), 2.63-2.81 (m, 3H), 3.01 (dd,J=18.31, 10.98 Hz, 2H), 3.27-3.35 (m, 1H), 3.36-3.45 (m, 1H), 3.58 (d,J=4.27 Hz, 1H), 3.70-3.85 (m, 4H), 3.93 (d, J=13.12 Hz, 1H), 4.24 (d,J=12.82 Hz, 1H), 6.94 (d, J=7.93 Hz, 1H), 7.03 (t, J=7.32 Hz, 1H), 7.20(d, J=7.32 Hz, 1H), 7.30-7.42 (m, 6H), 7.44-7.47 (m, 2H), 7.55 (d,J=7.32 Hz, 2H); MS (ESI+) m/z 418 (M+H)⁺.

Example 1313-benzyl-6-(2-methylbenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting2-methylbenzaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.36 (s, 3H), 2.53-2.62 (m, 1H), 2.64-2.76 (m,3H), 2.99 (d, J=10.68 Hz, 1H), 3.08 (d, J=10.68 Hz, 1H), 3.29-3.37 (m,1H), 3.37-3.49 (m, 1H), 3.54-3.60 (m, 1H), 3.64-3.77 (m, 2H), 3.81-3.90(m, 3H), 4.18 (d, J=13.12 Hz, 1H), 6.91 (d, J=7.93 Hz, 1H), 7.03 (t,J=7.17 Hz, 1H), 7.19-7.21 (m, 2H), 7.24-7.28 (m, 2H), 7.34 (t, J=7.17Hz, 2H), 7.39 (q, J=7.12 Hz, 2H), 7.46-7.50 (m, 1H), 7.56 (d, J=7.32 Hz,2H); MS (ESI+) m/z 398 (M+H)⁺.

Example 1323-benzyl-6-(2-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting2-bromobenzaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 2.61-2.67 (m, 1H) 2.69 (d, J=3.97 Hz, 2H) 2.85 (t,J=10.53 Hz, 1H) 3.12 (dd, J=32.04, 10.68 Hz, 2H) 3.29-3.37 (m, 1H)3.43-3.56 (m, 2H) 3.68-3.84 (m, 3H) 3.95 (s, 2H) 4.16 (d, J=13.12 Hz,1H) 6.90 (d, J=7.93 Hz, 1H) 7.03 (t, J=7.32 Hz, 1H) 7.13-7.18 (m, 1H)7.20 (s, 1H) 7.30-7.37 (m, 3H) 7.41 (t, J=7.48 Hz, 2H) 7.60 (s, 2H) 7.65(d, J=7.63 Hz, 2H); MS (ESI+) m/z 462 (M+H)⁺.

Example 1333-benzyl-6-(2-methoxybenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting2-methoxybenzaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.26-2.44 (m, 2H), 2.87 (dd, J=27.31, 10.83 Hz,2H), 2.97-3.10 (m, 2H), 3.37 (d, J=5.80 Hz, 2H), 3.59-3.69 (m, 5H),3.82-3.89 (m, 1H), 4.21-4.38 (m, 3H), 4.54 (d, J=12.82 Hz, 1H), 6.89 (d,J=8.24 Hz, 1H), 6.94 (d, J=7.93 Hz, 1H), 7.00 (t, J=7.48 Hz, 2H),7.29-7.43 (m, 6H), 7.49 (d, J=7.02 Hz, 2H), 7.78 (dd, J=7.48, 1.37 Hz,1H); MS (ESI+) m/z 414 (M+H)⁺.

Example 1343-benzyl-6-(4-methoxybenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting4-methoxybenzaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.34-2.46 (m, 1H), 2.56 (s, 1H), 2.87-3.09 (m,4H), 3.24-3.50 (m, 2H), 3.64-3.68 (m, 3H), 3.68-3.77 (m, 3H), 4.04-4.17(m, 2H), 4.28 (d, J=13.12 Hz, 1H), 4.48 (d, J=13.12 Hz, 1H), 6.92-6.99(m, 3H), 7.04 (t, J=7.32 Hz, 1H), 7.31 (t, J=7.17 Hz, 2H), 7.39 (t,J=7.48 Hz, 3H), 7.50 (d, J=7.32 Hz, 2H), 7.58-7.62 (m, 2H); MS (ESI+)m/z 414 (M+H)⁺.

Example 1353-benzyl-6-(3-methoxybenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting3-methoxybenzaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.42-2.50 (m, 1H), 2.55-2.67 (m, 1H), 2.81-3.01(m, 4H), 3.23-3.40 (m, 2H), 3.63-3.69 (m, 1H), 3.70-3.79 (m, 5H),3.95-4.09 (m, 2H), 4.15 (d, J=13.12 Hz, 1H), 4.39 (d, J=13.12 Hz, 1H),6.93 (d, J=7.93 Hz, 1H), 6.98 (dd, J=8.24, 2.14 Hz, 1H), 7.03 (t, J=7.32Hz, 1H), 7.16 (d, J=7.32 Hz, 1H), 7.25 (d, J=7.32 Hz, 1H), 7.29-7.42 (m,6H), 7.52 (d, J=7.32 Hz, 2H); MS (ESI+) m/z 414 (M+H)⁺.

Example 1363-benzyl-6-(3-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting3-bromobenzaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 2.51-2.56 (m, 1H), 2.58-2.77 (m, 3H), 2.81 (none,1H), 2.95 (d, J=10.68 Hz, 1H), 3.02 (d, J=10.98 Hz, 1H), 3.26-3.33 (m,1H), 3.36-3.42 (m, 1H), 3.46-3.53 (m, 1H), 3.68 (q, J=13.73 Hz, 2H),3.76-3.87 (m, 3H), 4.18 (d, J=13.12 Hz, 1H), 6.92 (d, J=7.93 Hz, 1H),7.02 (t, J=7.32 Hz, 1H), 7.16 (d, J=7.32 Hz, 1H), 7.21-7.26 (m, 1H),7.31-7.36 (m, 2H), 7.40 (t, J=7.48 Hz, 3H), 7.50 (d, J=7.93 Hz, 1H),7.55 (d, J=7.32 Hz, 2H), 7.76 (s, 1H); MS (ESI+) m/z 462 (M+H)⁺.

Example 1373-benzyl-6-(4-methylbenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting4-methylbenzaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.22 (s, 3H), 2.38-2.48 (m, 1H), 2.58 (s, 1H),2.83-3.04 (m, 4H), 3.25-3.45 (m, 2H), 3.64-3.77 (m, 3H), 4.05 (q,J=12.92 Hz, 2H), 4.21 (d, J=13.12 Hz, 1H), 4.42 (d, J=13.12 Hz, 1H),6.94 (d, J=7.93 Hz, 1H), 7.04 (t, J=7.32 Hz, 1H), 7.15 (d, J=7.93 Hz,2H), 7.25-7.34 (m, 2H), 7.35-7.41 (m, 3H), 7.51 (d, J=7.63 Hz, 4H); MS(ESI+) m/z 398 (M+H)⁺.

Example 1383-benzyl-6-(1-naphthylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting1-naphthaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 2.56-2.63 (m, 1H), 2.67-2.77 (m, 3H), 2.97 (d,J=10.68 Hz, 1H), 3.14 (d, J=10.68 Hz, 1H), 3.32 (d, J=12.51 Hz, 1H),3.41-3.49 (m, 1H), 3.52-3.59 (m, 1H), 3.82-3.92 (m, 3H), 4.10 (q,J=13.12 Hz, 2H), 4.19 (d, J=12.82 Hz, 1H), 6.90 (d, J=7.93 Hz, 1H), 7.04(t, J=7.32 Hz, 1H), 7.20 (s, 1H), 7.30-7.37 (m, 2H), 7.40 (t, J=7.32 Hz,2H), 7.47-7.57 (m, 4H), 7.59-7.63 (m, 2H), 7.90 (d, J=8.24 Hz, 1H), 7.97(d, J=7.93 Hz, 1H), 8.46 (d, J=8.24 Hz, 1H); MS (ESI+) m/z 398 (M+H).

Example 1393-benzyl-6-(2-chlorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting2-chlorobenzaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.56-2.66 (m, 1H), 2.70 (d, J=3.66 Hz, 2H), 2.80(t, J=10.37 Hz, 1H), 3.09 (dd, J=27.92, 10.83 Hz, 2H), 3.28-3.38 (m,1H), 3.41-3.48 (m, 1H), 3.50-3.56 (m, 1H), 3.69-3.94 (m, 5H), 4.18 (d,J=12.82 Hz, 1H), 6.91 (d, J=7.93 Hz, 1H), 7.03 (t, J=7.32 Hz, 1H), 7.20(s, 1H), 7.24 (dd, J=7.78, 1.68 Hz, 1H), 7.26-7.37 (m, 3H), 7.37-7.47(m, 3H), 7.57 (s, 2H), 7.64-7.69 (m, 1H); MS (ESI+) m/z 418 (M+H)⁺.

Example 1403-benzyl-6-(3-chlorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting3-chlorobenzaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.47-2.77 (m, 4H), 2.99 (d, J=10.68 Hz, 1H),3.05 (d, J=10.98 Hz, 1H), 3.26-3.34 (m, 1H), 3.37-3.46 (m, 1H),3.49-3.57 (m, 1H), 3.65-3.78 (m, 2H), 3.80-3.88 (m, 3H), 4.20 (d,J=13.12 Hz, 1H), 6.92 (d, J=7.93 Hz, 1H), 7.03 (t, J=7.17 Hz, 1H), 7.17(d, J=6.10 Hz, 1H), 7.26-7.43 (m, 7H), 7.56 (d, J=7.32 Hz, 2H), 7.60 (s,1H); MS (ESI+) m/z 418 (M+H)⁺.

Example 1413-benzyl-6-(2,2-dimethylpropyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substitutingpivalaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 0.92 (s, 9H), 2.27-2.36 (m, 1H), 2.39-2.45 (m, 1H),2.48-2.65 (m, 2H), 2.75-2.90 (m, 2H), 2.96 (d, J=10.07 Hz, 2H),3.31-3.43 (m, 2H), 3.44-3.54 (m, 1H), 3.71-3.85 (m, 2H), 3.96 (d,J=12.21 Hz, 1H), 4.24 (d, J=12.51 Hz, 1H), 6.94 (d, J=7.93 Hz, 1H), 7.03(t, J=7.32 Hz, 1H), 7.26 (d, J=7.32 Hz, 1H), 7.33 (t, J=7.48 Hz, 2H),7.40 (t, J=7.48 Hz, 2H), 7.56 (d, J=7.32 Hz, 2H); MS (ESI+) m/z 364(M+H)⁺.

Example 1423-benzyl-6-[(3-methyl-2-thienyl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting3-methylthiophene-2-carbaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹HNMR (500 MHz, pyridine-d₅) δ ppm 2.11-2.19 (m, 3H), 2.52-2.81 (m, 4H),3.02 (dd, J=37.38, 11.14 Hz, 2H), 3.28-3.34 (m, 1H), 3.37-3.44 (m, 1H),3.48-3.54 (m, 1H), 3.75-3.93 (m, 5H), 4.25 (d, J=13.12 Hz, 1H),6.84-6.93 (m, 2H), 7.02 (t, J=7.48 Hz, 1H), 7.18 (d, J=6.10 Hz, 1H),7.29-7.37 (m, 3H), 7.40 (t, J=7.32 Hz, 2H), 7.55 (t, J=6.71 Hz, 2H); MS(ESI+) m/z 404 (M+H)⁺.

Example 1433-benzyl-6-(3-methylbutyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting3-methylbutanal for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 0.81 (dd, J=6.56, 1.98 Hz, 6H), 1.46-1.56 (m, 1H),1.70-1.77 (m, 2H), 2.26-2.34 (m, 1H), 2.42 (d, 1H), 2.82 (d, J=10.68 Hz,1H), 2.97 (d, J=10.68 Hz, 1H), 3.01-3.20 (m, 4H), 3.26-3.33 (m, 2H),3.51-3.80 (m, 3H), 4.38-4.69 (m, 2H), 6.98 (d, J=7.93 Hz, 1H), 7.05 (t,J=7.32 Hz, 1H), 7.32 (t, J=7.32 Hz, 1H), 7.38-7.44 (m, 4H), 7.48 (d,J=7.32 Hz, 2H); MS (ESI+) m/z 364 (M+H)⁺.

Example 1443-benzyl-6-(cyclohexylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substitutingcyclohexanecarbaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 0.88-1.21 (m, 5H), 1.44-1.61 (m, 3H), 1.74-2.04(m, 3H), 2.24-2.36 (m, 2H), 2.75-2.89 (m, 3H), 2.93-3.11 (m, 3H),3.26-3.40 (m, 2H), 3.54-3.70 (m, 2H), 3.76-3.90 (m, 1H), 4.51 (s, 2H),6.97 (d, J=7.93 Hz, 1H), 7.04 (t, J=7.32 Hz, 1H), 7.29-7.43 (m, 5H),7.49 (d, J=7.32 Hz, 2H); MS (ESI+) m/z 390 (M+H)⁺.

Example 1453-benzyl-6-(3-methylbenzyl),-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting3-methylbenzaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.26 (s, 3H), 2.42-2.49 (m, 1H), 2.60 (s, 1H),2.82-2.98 (m, 4H), 3.22-3.42 (m, 2H), 3.66-3.79 (m, 3H), 3.96-4.09 (m,2H), 4.19 (d, J=13.12 Hz, 1H), 4.41 (d, J=12.82 Hz, 1H), 6.94 (d, J=7.93Hz, 1H), 7.04 (t, J=7.17 Hz, 1H), 7.13 (d, J=7.32 Hz, 1H), 7.26-7.44 (m,8H), 7.51 (d, J=7.32 Hz, 2H); MS (ESI+) m/z 398 (M+H)⁺.

Example 1463-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methyl]benzonitrile

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substituting3-formylbenzonitrile for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.55-2.75 (m, 4H), 2.99 (d, J=10.68 Hz, 1H),3.07 (d, J=10.98 Hz, 1H), 3.28-3.36 (m, 1H), 3.38-3.46 (m, 1H),3.46-3.54 (m, 1H), 3.60-3.78 (m, 3H), 3.81-3.88 (m, 2H), 4.15 (d,J=12.82 Hz, 1H), 6.93 (d, J=7.93 Hz, 1H), 7.04 (t, J=7.17 Hz, 1H), 7.16(d, J=7.02 Hz, 1H), 7.29-7.45 (m, 5H), 7.57 (d, J=7.32 Hz, 2H), 7.63(dd, J=17.55, 7.78 Hz, 2H), 7.81 (s, 1H); MS (ESI+) m/z 409 (M+H)⁺.

Example 1473-benzyl-6-(2-thienylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substitutingthiophene-2-carbaldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.53-2.60 (m, 1H), 2.63-2.85 (m, 3H), 3.04 (dd,J=29.90, 10.98 Hz, 2H), 3.25-3.33 (m, 1H), 3.36-3.46 (m, 1H), 3.48-3.55(m, 1H), 3.78-3.89 (m, 2H), 3.93-4.04 (m, 3H), 4.28 (d, J=13.12 Hz, 1H,6.90 (d, J=7.93 Hz, 1H), 6.99-7.05 (m, 2H), 7.12-7.18 (m, 2H), 7.29-7.46(m, 5H), 7.56 (d, J=7.32 Hz, 2H); MS (ESI+) m/z 390 (M+H)⁺.

Example 1483-benzyl-6-isobutyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 119 substitutingisobutyraldehyde for 4-methoxy-3-methylbenzaldehyde. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 0.95 (d, J=6.41 Hz, 6H), 1.92-2.06 (m, 1H), 2.29-2.44(m, 2H), 2.63-2.76 (m, 2H), 2.81-3.03 (m, 4H), 3.29-3.36 (m, 2H),3.58-3.70 (m, 2H), 3.71-3.81 (m, 1H), 4.17-4.52 (m, 2H), 6.97 (d, J=7.93Hz, 1H), 7.02 (t, J=7.32 Hz, 1H), 7.32 (t, J=6.71 Hz, 2H), 7.36-7.42 (m,3H), 7.50 (d, J=7.32 Hz, 2H); MS (ESI+) m/z 350 (M+H)⁺.

Example 1493-benzyl-N-(2-methoxyethyl)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

To a solution of triphosgene (22 mg, 0.074 mmol) in tetrahydrofuran (1mL) was added3-benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine(66 mg, 0.22 mmol, Example 2) in a tetrahydrofuran (1.0 mL) anddiisopropylethylamine (118 μL, 0.68 mmol). The reaction mixture wasshaken at room temperature for fifteen minutes. To the reaction mixturewas added 2-methoxy-N-methylethanamine (30 mg, 0.33 mmol). The reactionmixture was allowed to stir at room temperature overnight. The reactionwas filtered, checked by LC/MS and concentrated to dryness. Purificationof the residue via reverse phase HPLC afforded the title compound as thetrifluoroacetic acid salt. ¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.53 (t,1H), 2.69 (t, J=10.22 Hz, 1H), 2.86 (s, 3H), 3.00 (d, J=10.07 Hz, 2H),3.13-3.27 (m, 7H), 3.33 (t, 1H), 3.44-3.59 (m, 2H), 3.65-3.84 (m, 4 H),4.39 (d, J=12.51 Hz, 1H), 4.85 (d, J=12.51 Hz, 1H), 6.91 (d, J=7.63 Hz,1H), 7.03 (t, J=7.48 Hz, 1H), 7.23 (d, J=6.41 Hz, 1H), 7.30-7.36 (m,2H), 7.39 (t, J=7.32 Hz, 2H), 7.53 (d, J=7.32 Hz, 2H); MS (ESI+) m/z 409(M+H)⁺.

Example 1503-benzyl-N-[2-(pyridin-3-yl)ethyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substituting2-(pyridine-3-yl)-ethanamine for 2-methoxy-N-methylethanamine. ¹H NMR(500 MHz, pyridine-d₅) δ ppm 2.58-2.69 (m, 1H), 2.85 (t, J=10.83 Hz,1H), 2.91-3.06 (m, 3H), 3.06-3.20 (m, 3H), 3.32-3.47 (m, 2H), 3.66-3.79(m, 2H), 3.84-3.92 (m, 1H), 3.94-4.03 (m, 1H), 4.31 (d, J=14.95 Hz, 1H),4.52 (d, J=11.60 Hz, 1H), 4.84 (d, J=11.60 Hz, 1H), 6.95 (d, J=7.63 Hz,1H), 7.04 (t, J=7.17 Hz, 2H), 7.17-7.21 (m, 2H), 7.29-7.40 (m, 4H),7.55-7.57 (m, 3H), 8.63 (dd, J=4.88, 1.53 Hz, 1H); MS (ESI+) m/z 442(M+H)⁺.

Example 1513-benzyl-N-[2-(pyridin-2-yl)ethyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substituting2-(pyridine-2-yl)-ethanamine for 2-methoxy-N-methylethanamine. ¹H NMR(500 MHz, pyridine-d₅) δ ppm 2.56-2.65 (m, 1H), 2.89 (t, J=10.83 Hz,1H), 2.98 (dd, J=14.95, 3.97 Hz, 1H), 3.07-3.31 (m, 5H), 3.33-3.47 (m,2H), 3.84 (d, J=13.43 Hz, 1H), 3.90-4.02 (m, 3H), 4.31 (d, J=14.95 Hz,1H), 4.52 (d, J=11.60 Hz, 1H), 4.84 (d, J=11.60 Hz, 1H), 6.95 (d, J=7.93Hz, 1H), 7.05 (t, J=7.17 Hz, 2H), 7.09 (dd, J=7.17, 5.34 Hz, 1H), 7.20(d, J=3.97 Hz, 1H), 7.27-7.41 (m, 4H), 7.50-7.57 (m, 3H), 8.63 (d,J=4.58 Hz, 1H); MS (ESI+) m/z 442 (M+H)⁺.

Example 1523-benzyl-N-[2-(pyridin-4-yl)ethyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substituting2-(pyridine-4-yl)-ethanamine for 2-methoxy-N-methylethanamine. ¹H NMR(500 MHz, pyridine-d₅) δ ppm 2.54-2.63 (m, 1H) 2.77 (t, J=10.83 Hz, 1H)2.91-3.04 (m, 3H), 3.04-3.16 (m, 3H), 3.27-3.46 (m, 2H), 3.69-3.79 (m,2H), 3.80-3.85 (m, 1H), 3.90-3.96 (m, 1H), 4.32 (d, J=14.95 Hz, 1H),4.53 (d, J=11.60 Hz, 1H), 4.85 (d, J=11.60 Hz, 1H), 6.97 (d, J=7.93 Hz,1H), 7.04 (t, J=7.17 Hz, 2H), 7.17-7.21 (m, 2H), 7.29-7.41 (m, 4H), 7.56(d, J=7.32 Hz, 2H), 8.67 (d, J=5.80 Hz, 2H); MS (ESI+) m/z 442 (M+H)⁺.

Example 1533-benzyl-N-(2-cyanoethyl)-N-cyclopropyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substituting3-(cyclopropylamino) propanenitrile for 2-methoxy-N-methylethanamine. ¹HNMR (500 MHz, pyridine-d₅) δ ppm 0.63 (s, 2H) 0.67-0.90 (m, 4H) 2.46 (d,J=3.05 Hz, 1H), 2.66 (t, J=10.07 Hz, 1H), 2.72-2.88 (m, 4H), 2.99 (dd,2H), 3.08-3.26 (m, 2H), 3.20-3.37 (m, 2H), 3.72-3.90 (m, 2H), 4.65 (d,J=12.51 Hz, 1H), 4.92 (d, J=12.51 Hz, 1H), 6.93 (d, J=7.63 Hz, 1H), 7.04(t, J=7.32 Hz, 1H), 7.28-7.37 (m, 2H), 7.34-7.48 (m, 3H), 7.52 (d,J=7.32 Hz, 2H); MS (ESI+) m/z 430 (M+H)⁺.

Example 154[4-(2-aminoethyl)-1H-imidazol-1-yl](3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substituting2-(1H-imidazol-4-yl)ethanamine propanenitrile for2-methoxy-N-methylethanamine. ¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.31(s, 2H), 2.52-2.79 (m, 2H), 2.86-3.08 (m, 2H), 3.06-3.29 (m, 4H),3.26-3.54 (m, 4H), 3.82 (s, 4H), 4.55 (s, 2H), 4.57-4.77 (m, 2H),6.87-7.00 (m, 1H), 7.00-7.11 (m, 1H), 7.23-7.32 (m, 2H), 7.29-7.41 (m,3H), 7.38-7.52 (m, 2H); MS (ESI+) m/z 431 (M+H)⁺.

Example 1553-benzyl-N-(pyridin-4-ylmethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substitutingpyridine-4-ylmethanamine propanenitrile for2-methoxy-N-methylethanamine. ¹H NMR (500 MHz, pyridine-d₅) δ ppm2.44-2.49 (m, 1 H), 2.73 (t, J=10.53 Hz, 1H), 2.98-3.15 (m, 4H), 3.20(d, J=10.37 Hz, 1H), 3.28-3.39 (m, 1H), 3.63-3.83 (m, 2H), 4.35 (d,J=14.65 Hz, 1H), 4.62-4.82 (m, 3H), 4.98-5.07 (m, 1H), 6.96-7.02 (m,1H), 7.06 (t, J=7.48 Hz, 1H), 7.26-7.32 (m, 2H), 7.33-7.39 (m, J=7.53,7.53, 7.53 Hz, 3H), 7.42-7.46 (m, 2H), 7.47-7.51 (m, J=7.17, 7.17 Hz,3H), 7.72-7.76 (m, 1H); MS (ESI+) m/z 428 (M+H)⁺.

Example 1563-benzyl-N-[(5-methyl-2-furyl)methyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substituting(5-methylfuran-2-yl)methanamine propanenitrile for2-methoxy-N-methylethanamine. ¹H NMR (500 MHz, pyridine-d₅) δ ppm 2.13(s, 3H), 2.28-2.37 (m, 1H), 2.63 (t, J=10.53 Hz, 1H), 2.91 (t, J=11.60Hz, 2H), 3.00-3.14 (m, 3H), 3.17-3.29 (m, 1H), 3.52 (d, J=13.12 Hz, 1H),3.61-3.67 (m, 1H), 4.32 (d, J=14.65 Hz, 1H), 4.59-4.71 (m, 2H),4.79-4.88 (m, 1H), 4.97 (d, J=11.59 Hz, 1H), 6.97 (d, J=7.93 Hz, 1H),7.03 (t, J=7.48 Hz, 1H), 7.19 (s, 1H), 7.28-7.42 (m, 6H), 7.47 (d,J=7.32 Hz, 2H); MS (ESI+) m/z 431 (M+H)⁺.

Example 1573-benzyl-N-ethyl-N-(2-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substitutingN-ethyl-2-methoxyethanamine propanenitrile for2-methoxy-N-methylethanamine. ¹H NMR (500 MHz, pyridine-d₅) δ ppm0.97-1.39 (m, 3H), 2.67 (s, 2H), 2.96 (dd, J=29.29, 10.37 Hz, 3H),3.20-3.36 (m, 4H), 3.35-3.55 (m, 4H), 3.55-3.91 (m, 6H), 4.57-4.79 (m,1H), 4.87 (d, J=12.82 Hz, 1H), 6.61-7.00 (m, 1H), 6.97-7.11 (m, 2H),7.24 (t, J=6.10 Hz, 2H), 7.27-7.38 (m, 3H), 7.36-7.47 (m, 2H); MS (ESI+)m/z 423 (M+H)⁺.

Example 1583-benzyl-N,N-diethyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substitutingdiethylamine for 2-methoxy-N-methylethanamine. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 1.09 (t, J=7.02 Hz, 6H), 2.30-2.52 (m, 2H), 2.89 (dd,J=20.75, 10.98 Hz, 2H), 3.03 (dd, J=14.04, 7.02 Hz, 2H), 3.06-3.22 (m,4H), 3.22-3.37 (m, 4H), 3.57-3.74 (m, 4H), 4.40 (d, J=12.82 Hz, 1H),4.85 (d, J=12.51 Hz, 1H), 7.24-7.37 (m, 2H), 7.32-7.45 (m, 3H), 7.49 (d,J=7.32 Hz, 2H); MS (ESI+) m/z 393 (M+H)⁺.

Example 1593-benzyl-N-(1,3-thiazol-2-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substitutingthiazole-2-amine for 2-methoxy-N-methylethanamine. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 2.26 (t, 2H), 2.85 (t, 1H), 3.05 (d, J=11.29 Hz, 2H),3.08-3.33 (m, 4H), 3.38-3.73 (m, 4H), 4.76 (s, 1H), 6.27 (d, J=5.19 Hz,1H), 6.64 (d, J=3.66 Hz, 1H), 6.95 (d, J=7.93 Hz, 1H), 6.97-7.12 (m,1H), 7.32 (s, 2H), 7.30-7.45 (m, 3H), 7.43-7.55 (m, 2H); MS (ESI+) m/z420 (M+H)⁺.

Example 1603-benzyl-N-(cyclopropylmethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substitutingcyclopropylmethanamine for 2-methoxy-N-methylethanamine. ¹H NMR (500MHz, pyridine-d₅) δ ppm 0.10-0.53 (m, 4H), 1.20 (s, 1H), 2.34-2.60 (m,2H), 2.72-3.12 (m, 4H), 3.10-3.43 (m, 4H), 3.62-3.88 (m, 4H), 4.18-4.42(m, 1H), 4.51-4.73 (m, 1H), 4.92 (d, J=11.59 Hz, 1H), 6.88-7.00 (m, 1H),7.00-7.10 (m, 1H), 7.23-7.35 (m, 2H), 7.29-7.45 (m, 3H), 7.53 (d, J=7.32Hz, 2H); MS (ESI+) m/z 391 (M+H)⁺.

Example 161(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(4-isopropylpiperazin-1-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substituting1-isopropylpiperazine for 2-methoxy-N-methylethanamine. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 1.20 (d, J=6.41 Hz, 6H), 2.33-2.65 (m, 2H), 2.80-2.98(m, 2H), 3.06-3.20 (m, 4H), 3.17-3.31 (m, 4H), 3.29-3.48 (m, 2H),3.63-3.78 (m, 4H), 3.77-3.89 (m, 2H), 4.45 (d, J=12.82 Hz, 1H), 4.83 (d,J=12.82 Hz, 1H), 6.93 (d, J=7.63 Hz, 1H), 7.03 (t, J=7.48 Hz, 1H),7.24-7.38 (m, 2H), 7.34-7.46 (m, 3H), 7.49 (d, J=7.02 Hz, 2H); MS (ESI+)m/z 448 (M+H)⁺.

Example 1623-benzyl-N-isobutyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substituting2-methylpropan-1-amine for 2-methoxy-N-methylethanamine. ¹H NMR (500MHz, pyridine-d₅) δ ppm 0.94 (t, J=7.02 Hz, 6H), 1.82-2.12 (m, 1H),2.28-2.55 (m, 1H), 2.70 (t, J=10.68 Hz, 1H), 2.95-3.23 (m, 4H),3.20-3.52 (m, 4H), 3.52-3.87 (m, 2H), 4.34 (d, J=14.95 Hz, 1H), 4.64 (d,J=11.59 Hz, 1H), 4.95 (d, J=11.90 Hz, 1H), 6.90-7.04 (m, 1H), 7.05 (t,J=7.48 Hz, 1H), 7.20-7.31 (m, 2H), 7.31-7.44 (m, 3H), 7.50 (d, J=7.02Hz, 2H); MS (ESI+) m/z 393 (M+H).

Example 1633-benzyl-N-(pyridin-3-ylmethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substitutingpyridine-3-ylmethanamine for 2-methoxy-N-methylethanamine. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.35-2.61 (m, 1H), 2.75 (t, J=10.53 Hz, 1H),2.93-3.20 (m, 4H), 3.15-3.44 (m, 2H), 3.68-4.01 (m, 2H), 4.31 (d,J=13.43 Hz, 1H), 4.56-4.70 (m, 2H), 4.71-4.86 (m, 1H), 4.97 (d, J=11.59Hz, 1H), 6.97 (d, J=7.93 Hz, 1H), 7.05 (t, J=7.32 Hz, 1H), 7.23-7.28 (m,2H), 7.28-7.45 (m, 3H), 7.45-7.59 (m, 3H), 7.68 (t, J=5.80 Hz, 1H), 7.85(d, J=7.93 Hz, 1H), 8.65 (dd, J=4.73, 1.37 Hz, 1H), 8.95 (d, J=1.53 Hz,1H); MS (ESI+) m/z 428 (M+H)⁺.

Example 1643-benzyl-N-[3-(dimethylamino)propyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substitutingN,N-dimethylpropane-1,3-diamine for 2-methoxy-N-methylethanamine. ¹H NMR(500 MHz, pyridine-d₅) δ ppm 1.96-2.32 (m, 2H), 2.33-2.63 (m, 1H),2.67-2.85 (m, 7H), 2.93-3.15 (m, 4H), 3.16-3.42 (m, 4H), 3.47-3.75 (m,4H), 3.82 (s, 1H), 4.30 (d, 1H), 4.63 (d, J=111.90 Hz, 1H), 4.92 (d,J=11.90 Hz, 1H), 6.97 (d, J=7.93 Hz, 1H), 7.04 (t, J=7.48 Hz, 1H),7.23-7.30 (m, 2H), 7.32-7.45 (m, 3H), 7.53 (d, J=7.02 Hz, 2H); MS (ESI+)m/z 422 (M+H)⁺.

Example 1653-benzyl-N-butyl-N-(cyanomethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substituting2-(butylamino)acetonitrile for 2-methoxy-N-methylethanamine. ¹H NMR (500MHz, pyridine-d₅) δ ppm 0.83 (t, J=7.32 Hz, 3H), 1.06-1.26 (m, 2H),1.49-1.70 (m, 2H), 2.40 (d, J=2.14 Hz, 1H), 2.54 (dd, J=10.37, 8.85 Hz,1H), 2.67-2.91 (m, 2H), 3.03-3.42 (m, 6H), 3.48-3.67 (m, 2H), 3.85 (s,1H), 4.15-4.41 (m, 2H), 4.39-4.60 (m, 1H), 4.84 (d, J=13.12 Hz, 1H),6.96 (d, J=7.32 Hz, 2H), 7.25-7.40 (m, 2H), 7.34-7.41 (m, 3H), 7.49 (d,J=7.32 Hz, 2H); MS (ESI+) m/z 432 (M+H)⁺.

Example 1663-benzyl-N-(3-methoxypropyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substituting1-methoxypropane for 2-methoxy-N-methylethanamine. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 1.82-2.08 (m, 2H), 2.49 (d, J=2.44 Hz, 1H), 2.76 (s,1H), 2.92-3.13 (m, 4H), 3.13-3.32 (m, 3H), 3.31-3.48 (m, 4H), 3.50-3.65(m, 2H), 3.62-3.89 (m, 2H), 4.57 (d, J=11.60 Hz, 1H), 4.90 (d, J=11.90Hz, 1H), 6.97 (d, J=7.93 Hz, 1H), 7.05 (t, J=7.48 Hz, 1H), 7.28 (dd,J=41.65, 6.87 Hz, 2H), 7.32-7.44 (m, 3H), 7.52 (d, J=7.32 Hz, 2H); MS(ESI+) m/z 409 (M+H)⁺.

Example 1673-benzyl-N-(2-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substituting2-methoxyethanamine for 2-methoxy-N-methylethanamine. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 2.34-2.64 (m, 1H), 2.78 (s, 1H), 2.85-3.14 (m, 4H),3.16-3.40 (m, 4H), 3.45-3.68 (m, 4H), 3.68-3.91 (m, 4H), 4.31 (d, 1H),4.57 (d, J=11.90 Hz, 1H), 6.96 (d, J=7.93 Hz, 1H), 6.99-7.09 (m, 1H),7.31 (d, 2H), 7.37 (q, J=7.22 Hz, 3H), 7.52 (d, J=7.32 Hz, 2H); MS(ESI⁺) m/z 395 (M+H)⁺.

Example 1683-benzyl-N-(pyridin-2-ylmethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substitutingpyridin-2-ylmethanamine for 2-methoxy-N-methylethanamine. ¹H NMR (500MHz, pyridine-d₅) δ ppm 2.32-2.63 (m, 1H), 2.67-2.92 (m, 1H), 2.96-3.24(m, 4H), 3.24-3.48 (m, 2H), 3.69-3.96 (m, 2H), 4.35 (d, J=14.34 Hz, 1H),4.53-4.72 (m, 1H), 4.79-5.08 (m, 2H), 6.98 (d, J=7.93 Hz, 1H), 7.06 (t,J=7.32 Hz, 1H), 7.03-7.16 (m, 1H), 7.24-7.34 (m, 3H), 7.31-7.50 (m, 3H),7.50-7.59 (m, 5H); MS (ESI+) m/z 428 (M+H)⁺.

Example 1693-benzyl-N-cyclobutyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substitutingcyclobutanamine for 2-methoxy-N-methylethanamine. ¹H NMR (500 MHz,pyridine-d₅) δ ppm 1.22-1.62 (m, 4H), 1.71-1.94 (m, 1H), 1.94-2.11 (m,1H), 2.18-2.48 (m, 4H), 2.55-3.39 (m, 6H), 3.46-3.82 (m, 2H), 4.50-4.68(m, 1H), 4.91 (d, J=11.60 Hz, 1H), 6.97 (t, J=7.93 Hz, 1H), 6.97-7.10(m, 1H), 7.28-7.38 (m, 2H), 7.34-7.45 (m, 3H), 7.42-7.53 (m, 2H); MS(ESI+) m/z 391 (M+H)⁺.

Example 1703-benzyl-N-methyl-N-propyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substitutingN-methylpropan-1-amine for 2-methoxy-N-methylethanamine. ¹H NMR (500MHz, pyridine-d₅) δ ppm 0.80 (t, J=7.32 Hz, 3H), 1.27-1.60 (m, 1H), 2.46(d, J=3.05 Hz, 1H), 2.52-2.65 (m, 1H), 2.74 (s, 3H), 2.79-3.06 (m, 4H),3.10-3.25 (m, 4H), 3.29 (s, 2H), 3.38 (s, 2H), 3.54-3.76 (m, 3H), 4.84(d, J=12.51 Hz, 1H), 6.93 (d, J=7.63 Hz, 1H), 7.03 (t, J=7.48 Hz, 1H),7.25-7.37 (m, 2H), 7.33-7.44 (m, 3H), 7.49 (s, 2H); MS (ESI+) m/z 393(M+H)⁺.

Example 171(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(piperidin-1-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 149 substitutingpiperidine for 2-methoxy-N-methylethanamine. ¹H NMR (500 MHz, DMSO-d₆)δ=10.39 (s, 4H), 7.50 (dt, J=6.5, 3.4, 28H), 7.50 (dt, J=6.5, 3.4, 26H),7.35 (t, J=7.5, 6H), 7.35 (t, J=7.5, 5H), 7.28 (d, J=7.1, 6H), 7.28 (d,J=7.1, 5H), 7.02 (m, 11H), 7.02 (m, 11H), 4.60 (d, J=12.2, 6H), 4.60 (d,J=12.2, 5H), 4.45 (s, 11H), 4.45 (s, 10H), 4.13 (d, J=12.3, 5H), 4.13(d, J=12.3, 9H), 3.83 (s, 57H), 3.61 (m, 96H), 3.30 (m, 68H), 3.21 (m,30H), 2.99 (m, 19H), 2.94 (d, J=14.9, 5H), 2.50 (m, 6H), 1.51 (d,J=48.7, 29H), 1.51 (d, J=48.7, 30H), 1.30 (d, J=7.0, 3H), 1.06 (t,J=7.0, 1H); MS (ESI+) m/z 405.1 (M+H)⁺.

Example 1726-(cyclopropylmethyl)-2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one

To a solution of tert-butyl5-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate(100 mg, 0.315 mmol, Example 1) in anhydrous N,N-dimethylformamide (2mL) was added sodium hydride (13.86 mg, 0.347 mmol). After stirring for1 hour at room temperature, (bromomethyl)cyclopropane (102 mg, 0.756mmol) was added to the reaction mixture. The reaction was stirred for 20hours. The reaction was then quenched carefully with water and extractedwith ethyl acetate. The organic layer was separated, dried with MgSO₄,and concentrated. The residue was purified via flash chromatography(0-40% ethyl acetate/hexanes). The material obtained was dissolved in1,4-dioxane (0.8 mL) and 4 M HCl in 1,4-dioxane (0.8 mL). The mixturewas stirred for 20 hours. at room temperature. The title compound wascollected by filtration as the hydrochloric acid salt. ¹H NMR (500 MHz,DMSO-d₆) δ 9.44 (s, 1H), 8.19 (s, 1H), 7.07-6.94 (m, 1H), 6.89 (d, J=7.9Hz, 1H), 6.70 (t, J=7.2 Hz, 1H), 4.73 (d, J=16.0 Hz, 1H), 4.43 (s, 1H),4.17 (d, J=16.1 Hz, 1H), 3.51-2.79 (m, 8H), 0.66 (m, 1H), 0.15-0.05 (m,1H), 0.05-−0.08 (m, J=4.1 Hz, 1H); MS (DCI) m/z 221.1 (M+H)⁺.

Example 173[4-(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)piperidin-1-yl](phenyl)methanoneExample 173A3-methyl-1,2,3,4,4a,5,6,7-octahydrobenzo[f]pyrazino[1,2-a][1,4]diazepine

To a solution of tert-butyl5-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate(3 g, 9.45 mmol, Example 1) in tetrahydrofuran (95 mL) was added LiAlH₄in tetrahydrofuran (14.18 mL, 28.4 mmol), and the mixture was stirred atroom temperature for 24 hours. Water was added carefully and the productwas extracted once with dichloromethane. The organic phase was driedover Na₂SO₄ and concentrated to provide crude product which was purifiedby reverse phase HPLC to afford the title compound as thetrifluoroacetic acid salt. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.43 (s,1H), 9.29 (s, 2H), 7.46 (t, J=7.7, 1H), 7.33 (d, J=7.0, 1H), 7.13 (t,J=8.7, 2H), 4.33 (d, J=11.8, 1H), 4.21 (d, J=7.5, 1H), 3.41-2.93 (m,9H), 2.90 (s, 3H); MS (ESI+) m/z 218.0 (M+H)⁺.

Example 173B[4-(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)piperidin-1-yl](phenyl)methanone

To a solution of Example 173A (0.128 g, 0.589 mmol) in dichloromethane(4.53 mL) was added acetic acid (0.438 mL, 7.66 mmol),1-benzoylpiperidin-4-one (0.120 g, 0.589 mmol) and MP-cyanoborohydrideresin (1.414 g, 1.767 mmol), and the mixture was stirred at roomtemperature for 24 hours. The reaction mixture was filtered and theresin beads were washed with methanol. The filtrate was concentrated andpurified by reverse phase HPLC to afford the title compound as thetrifluoroacetic acid salt. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.35 (br s,1H), 7.58-7.33 (m, 7H), 7.20-6.99 (m, 2H), 5.02-3.96 (m, 7H), 3.13 (m,5H), 2.86 (s, 3H), 2.17 (br s, 1H), 1.69 (br s, 1H); MS (ESI+) m/z 405.1(M+H)⁺.

Example 174(2-chlorophenyl)(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methanone

To a solution of Example 173A (0.128 g, 0.589 mmol) in dichloromethane(3 mL) was added 2-chlorobenzoic acid (101 mg, 0.645 mmol),diisopropylethylamine (0.309 mL, 1.767 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.336 g, 0.884 mmol), and the reaction mixture wasstirred at room temperature for 24 hours. The reaction mixture wasfiltered, the filtrate was concentrated, and the crude residue waspurified by reverse phase HPLC to afford the title compound as thetrifluoroacetic acid salt. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.81 (br s,1H), 7.67-7.33 (m, 6H), 7.10 (m, 2H), 4.82-4.52 (m, 1H), 4.49-4.20 (m,1H), 3.77-3.48 (m, 1H), 3.32-2.74 (m, 11H); MS (ESI+) m/z 356.0 (M+H)⁺.

Example 175(3-chlorophenyl)(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 174 substituting3-chlorobenzoic acid for 2-chlorobenzoic acid. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 10.02-9.54 (m, 1H), 7.65-6.99 (m, 8H), 4.71-4.52 (m, 2H),4.38-4.15 (m, 1H), 3.63-3.37 (m, 3H), 3.19-2.71 (m, 8H); MS (ESI+) m/z356.0 (M+H)⁺.

Example 176(4-chlorophenyl)(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methanone

The title compound was prepared as the trifluoroacetic acid saltaccording to the procedure outlined in Example 174 substituting4-chlorobenzoic acid for 2-chlorobenzoic acid. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 7.76-6.99 (m, 8H), 4.62 (dd, J=21.8, 7.7, 2H), 4.30-4.12 (m, 1H),3.49 (m, 2H), 3.32-2.76 (m, 9H); MS (ESI+) m/z 356.0 (M+H).

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt or prodrug thereof, wherein R¹ isselected from the group consisting of hydrogen, alkyl, alkylcarbonyl,haloalkyl, G¹, —(CR^(4a)R^(5a))_(m)-G¹, —C(O)-G¹, —S(O)₂G¹, —C(O)OR⁶ and—C(O)NR⁷R⁸; wherein R¹ is other than hydrogen, alkyl, alkylcarbonyl, orhaloalkyl when one of Y¹ or Y² is CH₂ and the other is NR⁹; R², R³, R⁴,and R⁵ are each independently hydrogen, alkyl, alkenyl, alkynyl,halogen, cyano, —NO₂, —OR^(1a), —S(O)₂R^(2a), —C(O)OR^(1a), orhaloalkyl; R⁶ is alkyl or —(CR^(4a)R^(5a))_(m)-G¹; R⁷ and R⁸ areindependently hydrogen, alkyl, G¹, or —(CR^(4a)R^(5a))_(m)-G¹; R⁹ ishydrogen or alkyl; R^(1a), at each occurrence, is independentlyhydrogen, alkyl, haloalkyl, or —(CR^(4a)R^(5a))_(m)-G¹; R^(2a), at eachoccurrence, is independently alkyl, haloalkyl, or G¹; R^(4a) and R^(5a),at each occurrence, are each independently hydrogen, halogen, alkyl, orhaloalkyl, or R^(4a) and R^(5a) together with the carbon to which theyare attached form a cycloalkyl; R^(1b), at each occurrence, isindependently hydrogen, alkyl, or haloalkyl; R^(2b), at each occurrence,is independently alkyl, cyanoalkyl or haloalkyl; G¹, at each occurrence,is independently aryl or heteroaryl, wherein each G¹ is independentlyunsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selectedfrom the group consisting of alkyl, alkenyl, halogen, cyano, —NO₂,—OR^(1b), —S(O)₂R^(2b), —C(O)OR^(1b), —(CR^(4a)R^(5a))_(m)—N(R^(1b))₂,and haloalkyl; G², at each occurrence, is independently cycloalkyl orheterocycle, wherein each G² is independently unsubstituted orsubstituted with 1, 2, 3, 4, or 5 substituents selected from the groupconsisting of alkyl, alkenyl, halogen, cyano, —NO₂, —OR^(1b),—S(O)₂R^(2b), —C(O)OR^(1b), —C(O)R^(2b), —C(O)N(R^(1b))₂, haloalkyl, andoxo; m, at each occurrence, is independently 1, 2, 3, 4, or 5; X¹ is Nor CR⁵; one of Y¹ or Y² is CH₂ and the other is selected from the groupconsisting of NR⁹, N-G¹, N—(CR^(4a)R^(5a))_(m)-G¹,N⁺-[(CR^(4a)R^(5a))_(m)-G¹]₂, NC(O)—R^(2b),NC(O)—(CR^(4a)R^(5a))_(m)-G¹, NC(O)—(CR^(4a)R^(5a))_(m)—W¹,NC(O)—CH═CH-G¹, NC(O)-G¹, NC(O)-G²-G¹, N-G², N-G²-C(O)-G¹,N—(CR^(4a)R^(5a))_(m)-G², NC(O)—(CR^(4a)R^(5a))_(m)-G², NC(O)-G²,NC(O)NH—W³, NC(O)N(R^(2b))—W³, andNC(O)N(R^(1b))—(CR^(4a)R^(5a))_(m)—W²; wherein W¹ is NHC(O)G¹ or—O—(CR^(4a)R^(5a))_(m)—R^(1b); W² is G¹, G², N(R^(1b))₂, R^(1b), or—O—(CR^(4a)R^(5a))_(m)—R^(1b); W³ is R^(1b), G¹ or G²; and Y³ is CH₂ orC(O).
 2. The compound of claim 1, wherein X¹ is CR⁵; R⁵ is hydrogen; Y¹is CH₂; Y² is NR⁹, N-G¹, N—(CR^(4a)R^(5a))_(m)-G¹,N⁺-[(CR^(4a)R^(5a))_(m)-G¹]₂, NC(O)—(CR^(4a)R^(5a))_(m)-G¹,NC(O)—CH═CH-G¹, NC(O)-G¹, NC(O)-G²-G¹, N-G², N—(CR^(4a)R^(5a))_(m)-G²,NC(O)—(CR^(4a)R^(5a))_(m)-G², or NC(O)-G²; and Y³ is C(O).
 3. Thecompound of claim 2, wherein R¹ is selected from the group consisting ofhydrogen, —(CR^(4a)R^(5a))_(m)-G¹, —C(O)OR⁶; and Y² is NR⁹,N—(CR^(4a)R^(5a))_(m)-G¹ or N—(CR^(4a)R^(5a))_(m)-G².
 4. The compound ofclaim 1, wherein X¹ is CR⁵; R⁵ is hydrogen; and Y¹ and Y³ are each CH₂.5. The compound of claim 4, wherein R¹ is hydrogen, or—(CR^(4a)R^(5a))_(m)-G¹; and Y² is NR⁹.
 6. The compound of claim 4,wherein R¹ is hydrogen, —(CR^(4a)R^(5a))_(m)-G¹, or —C(O)OR⁶; Y² isN—(CR^(4a)R^(5a))_(m)-G, N—(CR^(4a)R^(5a))_(m)-G², orN⁺-[(CR^(4a)R^(5a))_(m)-G¹]₂; and m, at each occurrence, isindependently 1, 2, or
 3. 7. The compound of claim 4, wherein R¹ is—(CR^(4a)R^(5a))_(m)-G¹; Y² is N-G¹ or N-G²-C(O)-G¹; and m isindependently 1, 2, or
 3. 8. The compound of claim 4, wherein R¹ ishydrogen, alkyl, alkylcarbonyl, G¹, —(CR^(4a)R^(5a))_(m)-G¹, —C(O)-G¹,or —S(O)₂G¹; and Y² is NC(O)—(CR^(4a)R^(5a))_(m)-G¹, NC(O)—CH═CH-G¹,NC(O)-G¹, NC(O)-G²-G¹, NC(O)—(CR^(4a)R^(5a))_(m)-G²,NC(O)—(CR^(4a)R^(5a))_(m)—W¹, NC(O)—R^(2b) or NC(O)-G².
 9. The compoundof claim 4, wherein R¹ is hydrogen, alkyl, G¹, —(CR^(4a)R^(5a))_(m)-G¹,—C(O)-G¹, or —S(O)₂G¹; and Y² is NC(O)NH—W³, NC(O)N(R^(2b))—W³, andNC(O)N(R^(1b))—(CR^(4a)R^(5a))_(m)—W².
 10. The compound of claim 1,wherein Y² and Y³ are each CH₂.
 11. The compound of claim 10, wherein R¹is —(CR^(4a)R^(5a))_(m)-G¹; and Y¹ is NR⁹.
 12. The compound of claim 10,wherein R¹ is alkyl, —(CR^(4a)R^(5a))_(m)-G¹, or —C(O)-G¹; and Y¹ isN—(CR^(4a)R^(5a))_(m)-G¹, or N—(CR^(4a)R^(5a))_(m)-G².
 13. The compoundof claim 10, wherein X¹ is CR⁵ or N; R⁵ is hydrogen; R¹ is hydrogen,alkyl, or —(CR^(4a)R^(5a))_(m)-G¹; and Y¹ isNC(O)—(CR^(4a)R^(5a))_(m)-G¹, NC(O)-G¹, NC(O)—(CR^(4a)R^(5a))_(m)-G², orNC(O)-G².
 14. The compound of claim 1, wherein X¹ is CR⁵; and R², R³,R⁴, and R⁵ are each hydrogen.
 15. The compound according to claim 1 or apharmaceutically acceptable salt thereof, selected from the groupconsisting of: tert-butyl5-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate;3-benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-phenylethanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(phenyl)methanone;3,6,6-tribenzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepin-6-ium;3,6-dibenzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(pyrimidin-2-yl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(4-fluorophenyl)methanone;3-benzyl-6-(pyrazin-2-yl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(pyrazin-2-yl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1-phenylcyclopropyl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(morpholin-4-yl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)[trans-2-phenylcyclopropyl]methanone;3-benzyl-6-(pyridin-2-yl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;(−)-3-benzyl-6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;(+)-3-benzyl-6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;(2E)-1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-3-phenylprop-2-en-1-one;3-benzyl-6-[4-(trifluoromethyl)benzyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;7-(4-bromobenzyl)-3-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;3-benzyl-6-(4-bromo-3-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(3,5-difluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(3,4-difluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;1-(3-benzyl-2,3,4,4a,5,6-hexahydropyrazino[1,2-a][1,5]benzodiazepin-7(1H)-yl)-2-(4-chlorophenyl)ethanone;3-benzyl-6-(pyridin-3-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(pyridin-2-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(pyridin-4-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(4-bromophenyl)methanone;3-benzyl-6-[(6-methylpyridin-3-yl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(quinolin-3-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-[(6-chloropyridin-3-yl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(quinolin-4-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(isoquinolin-4-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-(4-fluorobenzyl)-2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one;3-benzyl-6-[(6-bromopyridin-3-yl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;(3-benzyl-2,3,4,4a,5,6-hexahydropyrazino[1,2-a][1,5]benzodiazepin-7(1H)-yl)(4-bromophenyl)methanone;3-benzyl-6-[(5-bromopyridin-2-yl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;(3-benzyl-2,3,4,4a,5,6-hexahydropyrazino[1,2-a][1,5]benzodiazepin-7(1H)-yl)(pyridin-4-yl)methanone;3-benzyl-7-[2-(4-chlorophenyl)ethyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;3,7-dibenzyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;3-benzyl-6-(4-iodobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-7-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;3-benzyl-7-(pyridin-4-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;3-benzyl-7-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,5]benzodiazepine;4-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methyl]phenol;9-benzyl-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;1-(9-benzyl-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl)-2-(4-chlorophenyl)ethanone;9-benzyl-5-[2-(4-chlorophenyl)ethyl]-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;9-benzyl-5-methyl-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;6-(4-bromobenzyl)-3-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;6-(4-bromobenzyl)-3-methyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;(9-benzyl-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl)(2,2,3,3-tetramethylcyclopropyl)methanone;9-benzyl-5-[(2,2,3,3-tetramethylcyclopropyl)methyl]-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-(6-chloropyridin-3-yl)ethanone;(+)-(4aS)-6-(4-bromobenzyl)-3-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;(−)-(4aR)-6-(4-bromobenzyl)-3-(4-fluorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-[2-(6-chloropyridin-3-yl)ethyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;5-(cyclopropylmethyl)-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;5-(cyclobutylmethyl)-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;tert-butyl6-(4-bromobenzyl)-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate;tert-butyl6-(4-bromobenzyl)-5-oxo-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepine-3(4H)-carboxylate;5-[(2S)-azetidin-2-ylmethyl]-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;5-(azetidin-3-ylmethyl)-9-(4-fluorobenzyl)-5,6,7,7a,8,9,10,11-octahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine;6-(4-bromobenzyl)-2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one;6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;cyclopropyl(7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl)methanone;6-(4-bromobenzyl)-3-(4-fluorobenzyl)-2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one;[5-(cyclopropylmethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-9(5H)-yl](pyridin-3-yl)methanone;1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl(morpholin-4-yl)methanone;[3-(4-fluorobenzyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl](morpholin-4-yl)methanone;(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(morpholin-4-yl)methanone;2-[2-(3-benzyl-2,3,4,4a,5,6-hexahydropyrazino[1,2-a][1,5]benzodiazepin-7(1H)-yl)-2-oxoethyl]pyridazin-3(2H)-one;(3-benzoyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(morpholin-4-yl)methanone;morpholin-4-yl[3-(pyrimidin-2-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl]methanone;morpholin-4-yl[3-(phenylsulfonyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl]methanone;[3-(4-chlorophenyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl](morpholin-4-yl)methanone;1-[6-(morpholin-4-ylcarbonyl)-1,2,4a,5,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-3(4H)-yl]ethanone;1-{4-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)carbonyl]piperidin-1-yl}ethanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1H-pyrazol-4-yl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1H-pyrazol-5-yl)methanone;1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-(morpholin-4-yl)ethanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1,3-thiazol-4-yl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1,3-thiazol-5-yl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1,2-oxazol-5-yl)methanone;1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-3-(pyrrolidin-1-yl)propan-1-one;1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-cyclopropylethanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1H-pyrrol-2-yl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(3-furyl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1,2,5-trimethyl-1H-pyrrol-3-yl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(2,5-dimethyl-1H-pyrrol-3-yl)methanone;1-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)carbonyl]cyclopropanecarboxamide;1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-(pyridin-3-yl)ethanone;N-[2-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-oxoethyl]-2-furamide;1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-methylpropan-1-one;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(3,5-dimethyl-1,2-oxazol-4-yl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(5-methylpyrazin-2-yl)methanone;1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-(4-methylpiperazin-1-yl)ethanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(2-furyl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1-methyl-1H-pyrrol-2-yl)methanone;1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)propan-1-one;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(pyridin-4-yl)methanone;1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)butan-1-one;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(tetrahydrofuran-3-yl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(pyridin-3-yl)methanone;1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-3-(piperidin-1-yl)propan-1-one;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(cyclopropyl)methanone;1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-2-ethoxyethanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(1-methylcyclopropyl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(cyclobutyl)methanone;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(2-methylcyclopropyl)methanone;1-(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)-3,3,3-trifluoropropan-1-one;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(tetrahydrofuran-2-yl)methanone;3-benzyl-6-(4-methoxy-3-methylbenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-[(4,5-dimethyl-2-furyl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(4-ethoxybenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-[(5-methyl-2-thienyl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(4-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(2-naphthylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(cyclopentylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(quinolin-2-ylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-[(5-ethyl-2-furyl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;4-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methyl]benzonitrile;3-benzyl-6-butyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(4-chlorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(2-methylbenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(2-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(2-methoxybenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(4-methoxybenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(3-methoxybenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(3-bromobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(4-methylbenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(1-naphthylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(2-chlorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(3-chlorobenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(2,2-dimethylpropyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-[(3-methyl-2-thienyl)methyl]-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(3-methylbutyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(cyclohexylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-(3-methylbenzyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-[(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methyl]benzonitrile;3-benzyl-6-(2-thienylmethyl)-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-6-isobutyl-1,2,3,4,4a,5,6,7-octahydropyrazino[1,2-a][1,4]benzodiazepine;3-benzyl-N-(2-methoxyethyl)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-[2-(pyridin-3-yl)ethyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-[2-(pyridin-2-yl)ethyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-[2-(pyridin-4-yl)ethyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-(2-cyanoethyl)-N-cyclopropyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;[4-(2-aminoethyl)-1H-imidazol-1-yl](3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methanone;3-benzyl-N-(pyridin-4-ylmethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-[(5-methyl-2-furyl)methyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-ethyl-N-(2-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N,N-diethyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-(1,3-thiazol-2-yl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-(cyclopropylmethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(4-isopropylpiperazin-1-yl)methanone;3-benzyl-N-isobutyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-(pyridin-3-ylmethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-[3-(dimethylamino)propyl]-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-butyl-N-(cyanomethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-(3-methoxypropyl)-1,2,3,4,4a,5-hcxahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-(2-methoxyethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-(pyridin-2-ylmethyl)-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-cyclobutyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;3-benzyl-N-methyl-N-propyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepine-6(7H)-carboxamide;(3-benzyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)(piperidin-1-yl)methanone;6-(cyclopropylmethyl)-2,3,4,4a,6,7-hexahydropyrazino[1,2-a][1,4]benzodiazepin-5(1H)-one;[4-(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)piperidin-1-yl](phenyl)methanone;(2-chlorophenyl)(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methanone;(3-chlorophenyl)(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methanone;and(4-chlorophenyl)(3-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-a][1,4]benzodiazepin-6(7H)-yl)methanone.16. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable carrier.